Great research starts with great data.

Learn More
More >
Patent Analysis of

CaMKK-β as a target for treating cancer

Updated Time 12 June 2019

Patent Registration Data

Publication Number

US9999620

Application Number

US15/185853

Application Date

17 June 2016

Publication Date

19 June 2018

Current Assignee

DUKE UNIVERSITY

Original Assignee (Applicant)

DUKE UNIVERSITY

International Classification

C07D471/04,A61K31/4745,C12N15/113,C07K16/30,G01N33/68

Cooperative Classification

A61K31/4745,A61K31/7088,C07K16/3069,C07K16/40,C12N15/1137

Inventor

MCDONNELL, DONALD P.,FRIGO, DANIEL,MEANS, ANTHONY R.

Patent Images

This patent contains figures and images illustrating the invention and its embodiment.

US9999620 CaMKK-β target 1 US9999620 CaMKK-β target 2 US9999620 CaMKK-β target 3
See all images <>

Abstract

Provided herein are compounds, compositions, including pharmaceutical compositions, having anti-cancer activity. Also provided are methods for diagnosing, detecting, and treating cancer in a subject, as well as a method for evaluating cancer stage in a subject, wherein the methods include determining the amount of a Ca2+/calmodulin dependent kinase kinase (CaMKK) in a sample. Further provided are methods of screening and identifying a compound that inhibits CaMKK.

Read more

Claims

1. A method of decreasing prostate cancer cell migration and invasion in a subject, the method comprising: administering to the subject an effective amount of a compound that inhibits activity of at least one of CaMKKβ, CaMKKβ splice variant 2, and CaMKKβ splice variant 7, wherein the compound is according to Formula III: wherein R1, R2, R3, R4, R5, R6, R7, R7a, R8, R9, R10, and R11 are each independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkylalkynyl, heterocyclo, heterocycloalkyl, heterocycloalkenyl, heterocycloalkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, alkoxy, halo, mercapto, azido, cyano, formyl, carboxylic acid, hydroxyl, nitro, acyl, aryloxy, alkylthio, amino, alkylamino, arylalkylamino, disubstituted amino, acylamino, acyloxy, ester, amide, sulfoxyl, sulfonyl, sulfonate, sulfonic acid, sulfonamide, urea, alkoxylacylamino, and aminoacyloxy; or a pharmaceutically acceptable salt or prodrug thereof.

2. The method of claim 1, wherein the compound inhibits the kinase activity of at least one of CaMKKβ, CaMKKβ splice variant 2, and CaMKKβ splice variant 7.

3. The method of claim 1, wherein the method decreases the activity of CaMKKβ and decreases the phosphorylation of AMPK.

4. The method of claim 1, wherein the compound inhibits the activity of CaMKKβ splice variant 2 or CaMKKβ splice variant 7.

5. The method of claim 1, wherein the compound specifically binds to CaMKKβ splice variant 2 or CaMKKβ splice variant 7.

6. The method of claim 1, wherein the compound is STO-609.

7. The method of claim 1, wherein the compound specifically binds to a C-terminal portion of CaMKKβ splice variant 2 polypeptide.

8. The method of claim 7, wherein the C-terminal portion of CaMKKβ splice variant 2 polypeptide is different from the C-terminal portion of splice variant 1 polypeptide.

9. The method of claim 1, wherein the compound specifically binds to a C-terminal portion of CaMKKβ splice variant 7 polypeptide.

10. The method of claim 9, wherein the C-terminal portion of CaMKKβ splice variant 7 polypeptide is different from the C-terminal portion of splice variant 1 polypeptide.

11. The method of claim 1, wherein the compound specifically binds to a portion of CaMKKβ splice variant 2 polypeptide encoded by exon 18.

12. The method of claim 1, wherein the compound specifically binds to a portion of CaMKKβ splice variant 7 polypeptide encoded by exon 18.

Read more

Claim Tree

  • 1
    1. A method of decreasing prostate cancer cell migration and invasion in a subject, the method comprising:
    • administering to the subject an effective amount of a compound that inhibits activity of at least one of CaMKKβ, CaMKKβ splice variant 2, and CaMKKβ splice variant 7, wherein the compound is according to Formula III: wherein R1, R2, R3, R4, R5, R6, R7, R7a, R8, R9, R10, and R11 are each independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkylalkynyl, heterocyclo, heterocycloalkyl, heterocycloalkenyl, heterocycloalkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, alkoxy, halo, mercapto, azido, cyano, formyl, carboxylic acid, hydroxyl, nitro, acyl, aryloxy, alkylthio, amino, alkylamino, arylalkylamino, disubstituted amino, acylamino, acyloxy, ester, amide, sulfoxyl, sulfonyl, sulfonate, sulfonic acid, sulfonamide, urea, alkoxylacylamino, and aminoacyloxy
    • or a pharmaceutically acceptable salt or prodrug thereof.
    • 2. The method of claim 1, wherein
      • the compound inhibits the kinase activity of at least one of CaMKKβ, CaMKKβ splice variant 2, and CaMKKβ splice variant 7.
    • 3. The method of claim 1, wherein
      • the method decreases the activity of CaMKKβ and decreases the phosphorylation of AMPK.
    • 4. The method of claim 1, wherein
      • the compound inhibits the activity of CaMKKβ splice variant 2 or CaMKKβ splice variant 7.
    • 5. The method of claim 1, wherein
      • the compound specifically binds to CaMKKβ splice variant 2 or CaMKKβ splice variant 7.
    • 6. The method of claim 1, wherein
      • the compound is STO-609.
    • 7. The method of claim 1, wherein
      • the compound specifically binds to a C-terminal portion of CaMKKβ splice variant 2 polypeptide.
    • 9. The method of claim 1, wherein
      • the compound specifically binds to a C-terminal portion of CaMKKβ splice variant 7 polypeptide.
    • 11. The method of claim 1, wherein
      • the compound specifically binds to a portion of CaMKKβ splice variant 2 polypeptide encoded by exon 18.
    • 12. The method of claim 1, wherein
      • the compound specifically binds to a portion of CaMKKβ splice variant 7 polypeptide encoded by exon 18.
See all independent claims <>

Description

FIELD

The disclosure relates to cancer, including diagnostic markers of cancer, methods for the diagnosis of cancer, methods and compounds for the treatment of cancer, methods for identifying cancer stage in a subject, methods for identifying a cancer that is responsive to particular therapies, and methods for evaluating efficacy of cancer therapy.

SEQUENCE LISTING

An electronic version of the sequence listing (“028193_9098_SeqList.txt”) which is 233,472 bytes in size and created on Aug. 16, 2011, is submitted herewith and is herein incorporated by reference.

BACKGROUND

Prostate cancer is the most common malignancy in men and is second only to lung cancer in terms of cancer mortalities [Cancer Facts and Figures: American Cancer Society; 2007.]. Early diagnosis of prostate cancer usually allows for successful surgical treatment of localized tumors and thus, good patient outcomes. However, as with many cancers, the treatment of the advanced disease state requires a systemic approach to inhibit the growth and spread of secondary metastases. Prostate cancers express the androgen receptor (AR) and rely on androgens for growth and survival [Isaacs J T, Isaacs W B., Nat Med 2004; 10:26-7.]. Consequently, androgen ablation therapies are the standard of care for late-stage disease. While 80% of patients with prostate cancer respond favorably to initial androgen ablation therapy, most patients experience a relapse of the disease within 1-2 years [Isaacs J T, Isaacs W B., Nat Med 2004; 10:26-7.]. Despite the unresponsiveness of the hormone-refractory disease to androgen-deprivation therapy, AR-regulated signaling pathways remain active and are necessary for cancer progression [Chen C. D., et al., Nature Med 2004; 10:33-9.].

Several approaches are currently used to target the AR signaling axis in prostate cancer. Existing therapies focus on decreasing the levels of circulating androgens and/or competitively blocking the AR transcriptional complex. Specifically, gonadotropin-releasing hormone (GnRH) agonists are used to suppress the testicular production of testosterone whereas antiandrogens, such as bicalutamide, function by competitively inhibiting the interaction of androgens with AR. The initial response to either form of androgen deprivation is very high. Nevertheless, the rapid onset of resistance to these interventions highlights the need for other strategies that target the hormone-independent activities of AR.

Most of the studies on the role of androgens in prostate cancer have focused on defining the mechanisms underlying the mitotic actions of this class of hormone [Balk S. P., Nucl Recept Signal 2008; 6:e001]. However, there is a growing body of evidence that AR signaling also influences tumor cell migration and invasion. For example, different clinical trials of goserelin (a GnRH analog) in prostate cancer patients demonstrate reduced incidences of distant metastases [Lawton C. A., et al. Int J Radiation Oncology Biol Phys 2001; 49:937-46; Bolla M., et al. The Lancet 2002; 360:103-8.]. Furthermore, it has recently been reported that MDV3100, a second generation AR-antagonist, decreases the number of circulating tumor cells in approximately half of the treated patients having a castration-resistant type cancer [Scher H. I., et al. The Lancet; 375:1437-46].

Compounds of Formula I are known and have been used as dye molecules. See, for example, U.S. Pat. No. 2,820,037 which describes:

wherein R1 is selected from CN, COOH, or COCl. The dye industry has generated a number of compounds that are structurally related to those of Formula I. See, e.g., U.S. Pat. Nos. 2,835,674; 2,965,644; 2,949,467; 3,953,452; 3,960,867; 4,239,868; and 4,336,383.

Japanese Patent Application No. 2003-012516 (Sumitomo Pharmaceutical Co.) identifies compounds as Ca2+/calmodulin dependent kinase kinase (CaMKK) inhibitors. The compounds are described as Formula II:

wherein R1 and R2 are independently selected from H, halo, alkyl, or haloalkyl; and R3 is H, alkyl, or substituted alkyl, or three COOR3 groups can be substituted at any location on the naphthalene ring.

U.S. Patent Application Publication No: 2010/0105716 discloses methods of treating obesity, insulin resistance, and hyperglycemia by administering a CaMKK inhibitor compound of Formula III:

wherein R1, R2, R3, R4, R5, R6, R7, R7a, R8, R9, R10, and R11 are each independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkylalkynyl, heterocyclo, heterocycloalkyl, heterocycloalkenyl, heterocycloalkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, alkoxy, halo, mercapto, azido, cyano, formyl, carboxylic acid, hydroxyl, nitro, acyl, aryloxy, alkylthio, amino, alkylamino, arylalkylamino, disubstituted amino, acylamino, acyloxy, ester, amide, sulfoxyl, sulfonyl, sulfonate, sulfonic acid, sulfonamide, urea, alkoxylacylamino, and aminoacyloxy; or a pharmaceutically acceptable salt or prodrug thereof.

None of these documents disclose or suggest that any of the compounds of Formula I-III would be useful in methods relating to cancer, or that CaMKKβ represents a therapeutic target in the treatment of cancers.

SUMMARY OF THE INVENTION

In an aspect, the disclosure provides a method of diagnosing prostate cancer in a subject comprising: determining an amount of at least one of CaMKKβ, CaMKKβ splice variant 2, CaMKKβ splice variant 7, phosphorylated AMPK, phosphorylated AMPKα1 subunit, and phosphorylated AMPKα2 subunit in a sample from the subject; and comparing the amount to a control sample comprising an amount of CaMKKβ, CaMKKβ splice variant 2, CaMKKβ splice variant 7, phosphorylated AMPK, phosphorylated AMPKα1 subunit, and phosphorylated AMPKα2 subunit in a control sample; wherein the subject is diagnosed as having prostate cancer when the amount of at least one of CaMKKβ, CaMKKβ splice variant 2, CaMKKβ splice variant 7, phosphorylated AMPK, phosphorylated AMPKα1 subunit, and phosphorylated AMPKα2 subunit in the sample from the subject is greater than the amount in the control sample.

In an aspect the disclosure relates to a method for determining disease stage in a subject having prostate cancer, the method comprising: determining an amount of at least one of CaMKKβ, CaMKKβ splice variant 2, CaMKKβ splice variant 7, phosphorylated AMPK, phosphorylated AMPKα1 subunit, and phosphorylated AMPKα2 subunit in a sample from the subject; and comparing the amount to a control sample comprising an amount of at least one of CaMKKβ, CaMKKβ splice variant 2, CaMKKβ splice variant 7, phosphorylated AMPK, phosphorylated AMPKα1 subunit, and phosphorylated AMPKα2 subunit; wherein the disease stage of prostate cancer is determined by the difference in the amount of at least one of CaMKKβ, CaMKKβ splice variant 2, CaMKKβ splice variant 7, phosphorylated AMPK, phosphorylated AMPKα1 subunit, and phosphorylated AMPKα2 subunit in the sample from the subject and the amount in the control sample.

Aspects also relate to a method for predicting the likelihood of success of hormone-based therapeutic treatment of a subject having prostate cancer, the method comprising determining an amount of at least one of CaMKKβ, CaMKKβ splice variant 2, CaMKKβ splice variant 7, phosphorylated AMPK, phosphorylated AMPKα1 subunit, and phosphorylated AMPKα2 subunit in a sample from the subject; and comparing the amount to a control sample comprising an amount of the CaMKKβ, CaMKKβ splice variant 2, CaMKKβ splice variant 7, phosphorylated AMPK, phosphorylated AMPKα1 subunit, and phosphorylated AMPKα2 subunit. Embodiments provide for a likely successful response to hormone-based therapeutic treatment when the amount of at least one of CaMKKβ, CaMKKβ splice variant 2, CaMKKβ splice variant 7, phosphorylated AMPK, phosphorylated AMPKα1 subunit, and phosphorylated AMPKα2 subunit in the sample from the subject is greater than the amount in the control sample.

In an aspect the disclosure relates to a method for early detection of prostate cancer in a subject comprising obtaining a sample from the subject; determining an amount of at least one of CaMKKβ, CaMKKβ splice variant 2, CaMKKβ splice variant 7, phosphorylated AMPK, phosphorylated AMPKα1 subunit, and phosphorylated AMPKα2 subunit in the sample from the subject; and comparing the amount of at least one of CaMKKβ, CaMKKβ splice variant 2, CaMKKβ splice variant 7, phosphorylated AMPK, phosphorylated AMPKα1 subunit, and phosphorylated AMPKα2 subunit from the sample from the subject to an amount of the CaMKKβ, CaMKKβ splice variant 2, CaMKKβ splice variant 7, AMPK, and AMPKα1 subunit in a control sample; wherein early detection of prostate cancer is made when the amount of at least one of CaMKKβ, CaMKKβ splice variant 2, CaMKKβ splice variant 7, phosphorylated AMPK, phosphorylated AMPKα1 subunit, and phosphorylated AMPKα2 subunit in the sample from the subject is greater than the amount in the control sample.

In another aspect the disclosure provides a method for identifying a selective inhibitor of CaMKKβ where the method includes contacting CaMKKβ and a substrate therefor, in the presence and in the absence of the test compound, under conditions such that CaMKKβ-dependent phosphorylation of the substrate can be effected, and determining the level of phosphorylation of the substrate resulting from the contacting, and comparing the amount of phosphorylated substrate with a level of phosphorylation of the substrate in the absence of the test compound, wherein an decrease in phosphorylation of the substrate in the presence of the test compound indicates that the test compound is a selective inhibitor of CaMKKβ.

In an aspect the disclosure provides a method of screening a test compound for anti-cancer activity comprising: contacting CaMKKβ and a substrate therefor in the presence of the test compound, under conditions that allow for CaMKKβ-dependent phosphorylation of the substrate; determining the level of phosphorylation of the substrate resulting from the contacting; and comparing that level with a level of phosphorylation of the substrate obtained in the absence of the test compound, wherein a reduction in the level of phosphorylation of the substrate in the presence of the test compound indicates that the test compound has anti-cancer activity.

In an aspect the disclosure provides a method of treating cancer in a subject, comprising administering to the subject an effective amount of a compound that inhibits activity of a CaMK biological cascade in the subject.

In an aspect the disclosure provides a method of treating cancer in a subject, comprising administering to the subject an effective amount of a compound that inhibits activity of at least one of CaMKK or AMPK.

In an aspect the disclosure provides a method of treating cancer in a subject, comprising administering to the subject an effective amount of a compound that inhibits activity of at least one of CaMKKβ, CaMKKβ splice variant 2, or CaMKKβ splice variant 7.

In a further aspect the disclosure provides a method of treating prostate cancer in a subject, comprising administering to the subject an effective amount of a compound that inhibits activity of a CaMK biological cascade in the subject.

In a further aspect the disclosure provides a method of treating prostate cancer in a subject, comprising administering to the subject an effective amount of a compound that inhibits activity of at least one of CaMKK or AMPK.

In a further aspect the disclosure provides a method of treating prostate cancer in a subject, comprising administering to the subject an effective amount of a compound that inhibits activity of at least one of CaMKKβ, CaMKKβ splice variant 2, or CaMKKβ splice variant 7.

In yet another aspect, the disclosure relates to a method of treating prostate cancer in a subject, the method comprising administering to the subject an effective amount of an inhibitor of phosphorylated AMPK, phosphorylated AMPKα1 subunit, or phosphorylated AMPKα2 subunit.

In another aspect, the disclosure provides a method of determining the efficacy of therapy in a patient being treated for prostate cancer, the method comprising: determining an amount of at least one of CaMKKβ, CaMKKβ splice variant 2, CaMKKβ splice variant 7, phosphorylated AMPK, phosphorylated AMPKα1 subunit, and phosphorylated AMPKα2 subunit in a series of samples from the subject, where the samples are taken from the subject at different time points during the therapy; and comparing the determined amount over the course of the time points; wherein when the amount of at least one of CaMKKβ, CaMKKβ splice variant 2, CaMKKβ splice variant 7, phosphorylated AMPK, phosphorylated AMPKα1 subunit, and phosphorylated AMPKα2 in the series of samples is about the same or increases over the course of the time points, the therapy is not effective.

In an aspect the disclosure provides a method of inhibiting androgen-mediated migration of a prostate cancer cell in a subject comprising administering to the subject an effective amount of a compound that inhibits activity of a CaMK biological cascade in the subject.

In an aspect the disclosure provides a method of inhibiting androgen-mediated migration of a prostate cancer cell in a subject comprising administering to the subject an effective amount of a compound that inhibits activity of at least one of CaMKK or AMPK.

In another aspect the disclosure provides a method of inhibiting androgen-mediated migration of a prostate cancer cell in a subject comprising administering to the subject an effective amount of an inhibitor of at least one of CaMKKβ, CaMKKβ splice variant 7, or CaMKKβ splice variant 2 or any combination thereof.

In an aspect the disclosure provides a method of inhibiting androgen-mediated invasion of a prostate cancer cell in a subject comprising administering to the subject an effective amount of a compound that inhibits activity of a CaMK biological cascade in the subject.

In an aspect the disclosure provides a method of inhibiting androgen-mediated invasion of a prostate cancer cell in a subject comprising administering to the subject an effective amount of a compound that inhibits activity of at least one of CaMKK or AMPK.

In an aspect the disclosure provides a method of inhibiting androgen-mediated invasion of a prostate cancer cell in a subject comprising administering to the subject an effective amount of an inhibitor of at least one of CaMKKβ, CaMKKβ splice variant 7, or CaMKKβ splice variant 2 or any combination thereof.

In an aspect the disclosure provides a method of inhibiting metastasis of prostate cancer in a subject comprising administering to the subject an effective amount of a compound that inhibits activity of a CaMK biological cascade in the subject.

In an aspect the disclosure provides a method of inhibiting metastasis of prostate cancer in a subject comprising administering to the subject an effective amount of a compound that inhibits activity of at least one of CaMKK or AMPK.

In an aspect the disclosure provides a method of inhibiting metastasis of prostate cancer in a subject comprising administering to the subject an effective amount of an inhibitor of at least one of CaMKKβ, CaMKKβ splice variant 7, or CaMKKβ splice variant 2 or any combination thereof.

Aspects also relate to a nucleic acid molecule comprising a sequence that binds under stringent conditions to a region that is about 2.3 kb upstream (5′) relative to a CaMKKβ transcriptional start site.

Further aspects relate to an antibody that specifically binds to a C-terminal portion of a CaMKKb.

Aspects also relate to polynucleotides (e.g., siRNA) that comprise a sequence that is complementary to CaMKKβ, CaMKKα, or AMPK and having kinase-inhibitory activity.

The disclosure provides for and encompasses additional aspects and embodiments, which will be apparent to those of skill in the art in light of the following description.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1. Androgens increase CaMKKβ levels in an AR-dependent manner. LNCaP or VCaP cells were treated for 24 h with vehicle or increasing concentrations of the synthetic androgen R1881 (A—0.1, 1, and 10 nM; B—0.01, 0.1, 1, and 10 nM). A, after treatment, cells were lysed, and RNA was isolated and reversed transcribed. The expression of CaMKKβ was assessed using qPCR. B, after treatment, cells were subjected to western blot analysis and subsequent densitometry (top). CaMKKβ protein levels were normalized to GAPDH loading control. A and B, results are expressed as fold induction over vehicle-treated cells+SE (n=3). *, significant changes from vehicle-treated cells. C, LNCaP cells were transiently transfected with mock or Stealth siRNAs targeting a negative control (siLacZ) or CaMKKβ (#1-3). Two days later, cells were treated for 24 h+/−10 nM R1881. Whole-cell extracts were subjected to western blot analysis and densitometry (top) as described in B. *, significant changes from mock-transfected cells. D, LNCaP cells were transfected as described in C with mock or Stealth siRNAs targeting LacZ or AR and treated for 24 h. The expression of CaMKKβ was assessed as in A using qPCR.

FIG. 2. Validation of CaMKKβ protein bands. For CaMKKβ western blot analysis, a different monoclonal CaMKKβ antibody (clone 1A11) was used than in FIG. 1. CaMKKβ protein levels were normalized to GAPDH loading control. Results are expressed as fold induction over vehicle-treated cells+SE (n=2). *, P<0.05 indicates significant changes from mock-transfected cells.

FIG. 3. CaMKKβ levels are increased in prostate cancer samples. Independent microarrays were analyzed using the Oncomine resource. A, four separate studies determined that CaMKKβ levels were elevated in prostate cancer samples (red) compared to normal prostate controls (blue). B, CaMKKβ levels correlated with disease progression. C, CaMKKβ levels are significantly higher in prostate cancer samples compared to other cancers (a—bladder, b—kidney, c—colon, d—breast, e—esophageal, f—liver, g—lung, h—ovarian, i—pancreatic, j—squamous cell lung). All changes in expression were at the P<0.001 level.

FIG. 4. The prostate expresses a different functional splice variant of CaMKKβ□ compared to brain. A, schematic of CaMKKβ splice variants. B, RT-PCR using primers spanning specific exons (indicated in right schematic) was performed on cDNA generated from various tissues and cell lines. C, LNCaP or VCaP cells were treated for 24 h+/−10 nM R1881. Cell lysates were then subjected to western blot analysis and subsequent densitometry (right). Phospho-CaMKI (p-CaMKI) protein levels were normalized to total CaMKI. Results are expressed as fold CaMKI phosphorylation over vehicle-treated cells+SE (n=3). *, significant changes from vehicle-treated cells.

FIG. 5. The prostate expresses different splice variants of CaMKKβ□compared □to □brain (expanded FIG. 4A and FIG. 4B). A, schematic of CaMKKβ splice variants. B, RT-PCR using primers spanning specific exon-exon boundaries (indicated in right schematic) was performed on cDNA generated from various tissues and cell lines.

FIG. 6. CaMKKβ activity in androgen-mediated cell migration in prostate cancer cells. A, LNCaP cells were pretreated for 1 h with vehicle, 10 or 30 mM STO-609 prior to overnight treatment with vehicle, 100 pM or 10 nM R1881. Cell lysates were then subjected to western blot analysis and subsequent densitometry (right). Phospho-CaMKI (p-CaMKI) levels were normalized to total CaMKI. Results are expressed as fold induction/phosphorylation over double vehicle-treated cells+SE (n=2). *, P<0.05 indicates significant changes from vehicle-treated cells. #, P<0.05 indicates significant changes from vehicle (no STO-609)-treated cells. B, VCaP cells were plated in 96-well plates and grown for 3 d. Cells were treated+/−1 nM R1881 and +/−30 mM STO-609 on d 3, d 5, and d 7. On d 10, cells were lysed and the relative number of cells was measured with the fluorescent DNA binding dye FluoReporter Blue. Each sample was performed in triplicate, and results from a representative experiment are shown. Results are expressed as relative cell number±SE (n=2). *, P<0.05 indicates significant changes from vehicle (no R1881)-treated cells. C, VCaP cells were pretreated for 1 h+/−30 mM STO-609 prior to overnight treatment+/−10 nM R1881. Cells were then dissociated and reseeded into the top chamber for a Boyden dual chamber migration assay. Fresh medium with the corresponding treatments was added to the top and bottom chambers while either no chemoattractant or 5% FBS (serum) was added to the bottom chamber. After 16 h, migrated cells were fixed, stained with crystal violet and counted in three different microscopic fields and added together. The results are expressed as mean±SE (n=2). *, P<0.05 indicates significant changes from vehicle (no R1881)-treated cells. D and E, densitometry results for western blots in FIG. 7C and FIG. 7D respectively. *, P<0.05 indicates significant changes from vehicle-treated (D) or GAL4 control (E) cells. #, P<0.05 indicates significant changes from control (siLacZ)-transfected cells (D).

FIG. 7. CaMKKβ activity in the androgen-mediated migration and invasion of prostate cancer cells. A, LNCaP cells were plated in 96-well plates and grown for 3 d. Cells were treated+/−1 nM R1881 and +/−30 mM STO-609 on d 3, d 5, and d 7. On d 10, cells were lysed and the relative number of cells was measured with the fluorescent DNA binding dye FluoReporter Blue. Each sample was performed in triplicate, and results from a representative experiment are shown. Results are expressed as relative cell number±SE (n=2). *, significant changes from vehicle (no R1881)-treated cells. B, LNCaP cells were pretreated for 1 h+/−30 mM STO-609 prior to overnight treatment+/−10 nM R1881. Cells were then dissociated and reseeded into the top chamber for a Boyden migration or Matrigel extracellular matrix invasion assay. Fresh medium with the corresponding treatments was added to the top and bottom chambers while either no chemoattractant or 5% FBS (serum) was added to the bottom chamber. After 16 h, migrated cells were fixed, stained and counted in three different microscopic fields and added together. The results are expressed as mean±SE (n=3). *, significant changes from vehicle (no R1881)-treated cells. #, significant changes from vehicle (no STO-609)-treated cells. C top, LNCaP cells were transfected with indicated siRNAs. Two days after transfection, cells were treated+/−10 nM R1881 and subjected to a Boyden migration assay as described in B. *, significant changes from vehicle-treated cells. #, significant changes from control (siLacZ)-transfected cells. C bottom, western blot to demonstrate CaMKKβ□ knockdown. Quantification of these blots is presented in FIG. 6D. D right, LNCaP cells stably expressing either GAL4 (control) or CaMKKβ were subjected to a migration assay as described in B using +/−5% FBS as chemoattractant. The results are expressed as mean+SE (n=3). *, significant changes from LNCaP-GAL4 cells. D left, western blot confirming CaMKKβ□expression. Quantification of these blots is presented in FIG. 6E.

FIG. 8. Androgen mediated prostate cancer cell migration and functional AR-mediated transcription. A and B, an example of the AR replacement strategy is shown. This method has the advantage of using cells with endogenous androgen signaling as opposed to the common reintroducing of AR into AR-negative cells, which often has artificial biological consequences. Here, cells that express endogenous AR, in this case LNCaPs, were retrovirally infected to create stable cell lines expressing a control (GAL4) or a v5-tagged version of AR (wild type or a DNA-binding domain mutant (C562S)) linked to an IRES-EGFP. Cells were then selected using 2 rounds of flow cytometry. Subsequently, EGFP-positive cells were transfected with chemical siRNAs targeting either a control sequence (siLacZ) or the 3′-UTR of AR (eliminates endogenous receptor). A, a western blot characterization of the resultant cell lines is shown at the right using antibodies for v5 (recognizes only exogenous AR), AR (recognizes both exogenous and endogenous AR) or GAPDH (loading control). B, LNCaP cells used in the AR replacement experiments were also subjected to qPCR analysis using primers targeting the AR 3′UTR (monitors endogenous AR levels). The expression of AR was normalized to 36B4 levels and results are expressed as relative mRNA levels of AR compared to mock-transfected cells+SE (n=2). *, P<0.05 indicates significant changes from mock-transfected cells. C, cells were then subjected to a migration assay as described in FIG. 9. *, P<0.05 indicates significant changes from vehicle-treated cells.

FIG. 9. Identification of the ARE that regulates CaMKKβ expression. A, LNCaP cells were pretreated for 1 h with vehicle or 1 mg/mL cycloheximide followed by vehicle or 10 nM R1881 for 24 h. CaMKKβ or CXCR4 mRNA levels were quantified using qPCR. Results are expressed as fold induction over vehicle (no R1881)-treated cells±SE (n=3). *, significant changes from vehicle-treated cells. B, LNCaP cells were treated with vehicle (V) or 10 nM R1881 for 1 or 4 h. Cross-linked chromatin was immunoprecipitated with indicated antibodies. The precipitated DNA was amplified using primers spanning a region identified using ChIP on Chip data as a potential AR-binding site (indicated in top schematic) or a distal upstream region (negative control). The results are presented as percent input±SE (n=3). *, significant changes from IgG controls. C, various enhancer luciferase reporter constructs (depicted in top model) were transfected into LNCaP cells and treated overnight+/−10 nM R1881. After treatment, cells were harvested and assayed for luciferase activity. Luciferase values were normalized to β-galactosidase control. Data are the mean relative light units (RLUs)+SEM for one representative experiment performed in triplicate (n=3). *, significant changes from vehicle-treated cells. D, CaMKKβ promoter constructs (depicted in top model) were transfected into LNCaP cells and then treated overnight with vehicle or 10 nM R1881. After treatment, cells were harvested and assayed for luciferase activity as in C. Emp Vec, empty vector.

FIG. 10. Identification of the ARE that regulates CaMKKβ expression. A, two CaMKKβ enhancer (fragments D and E from FIG. 9C) luciferase reporter constructs were transfected into LNCaP cells and then pretreated for 30 minutes with vehicle or 10 mM Casodex followed by treatment overnight with vehicle or various concentrations of R1881 (0, 0.1, 1 and 10 nM). After treatment, cells were harvested and assayed for luciferase activity. Luciferase values were normalized to β-galactosidase control. Data are the mean relative light units (RLUs)+SEM for one representative experiment performed in triplicate (n=3). *, P<0.05 indicates significant changes from vehicle (no R1881)-treated cells. #P<0.05 indicates significant changes from vehicle (no Casodex)-treated cells. B, VCaP cells were transfected, treated and assayed for luciferase activity as in A using the PSA enhancer and CaMKKβ enhancer fragments D and E. C, CaMKKβ enhancer deletion constructs were transfected into LNCaP cells and then treated and assayed for luciferase activity as in A (n=2). Emp Vec, empty vector.

FIG. 11. Androgen-mediated migration occurs through a CaMKKβ-AMPK-dependent pathway. A, LNCaP cells were pretreated for 1 h+/−30 mM STO-609 prior to overnight treatment+/−10 nM R1881. Cell lysates were then subjected to western blot analysis and subsequent densitometry (right). CaMKKβ levels were normalized to GAPDH. Phospho-CaMKI (p-CaMKI) levels were normalized to total CaMKI. Phospho-AMPK (p-AMPK) levels were normalized to total AMPK. Results are expressed as fold induction/phosphorylation over double vehicle-treated cells+SE (n=3). *, significant changes from vehicle-treated cells. B, LNCaP cells stably expressing either GAL4 or CaMKKβ□were treated overnight+/−10 nM R1881. Cell lysates were then subjected as in A to western blot analysis and densitometry (right). Results are expressed as fold induction/phosphorylation over LNCaP-GAL4 vehicle-treated cells+SE (n=3). *, significant changes from LNCaP-GAL4 vehicle-treated cells. C and D, LNCaP cells were transfected with indicated siRNAs, treated and subjected to a migration assay (top) or western blot analysis (bottom) as in FIG. 7C. *, significant changes from control (siLacZ)-transfected cells. Quantification of the blots is presented in FIG. 12.

FIG. 12. Androgen-mediated migration occurs through a CaMKKβ-AMPK-dependent pathway. A, VCaP cells were treated for 24 h+/−10 nM R1881. Cell lysates were then subjected to western blot analysis and subsequent densitometry (right). Phospho-CaMKI (p-CaMKI) levels were normalized to total CaMKI. Phospho-AMPK (p-AMPK) levels were normalized to total AMPK. Results are expressed as fold induction/phosphorylation over vehicle-treated cells+SE (n=2). *, P<0.05 indicates significant changes from vehicle-treated cells. B, selection of optimal AMPKα1 and α2 siRNAs. LNCaP cells were transfected as described in FIG. 11 with mock or Stealth siRNAs targeting LacZ (negative control) or AMPKα1 or α2. The expression of AMPK was assessed using qPCR and normalized to 36B4 levels. Results are expressed as fold induction over mock-transfected cells+SE (n=2). *, P<0.05 indicates significant changes from mock-transfected cells. C and D, densitometry results for western blots in FIG. 11C and FIG. 11D, respectively. For AMPKa knockdown (C), siAMPKα1-#1 and siAMPKα2-#1 from B were selected since they produced the greatest knockdowns. *, P<0.05 indicates significant changes from control (siLacZ)-transfected cells.

FIG. 13. AMPK and androgen-mediated prostate cancer cell migration. A, LNCaP cells were pretreated for 1 h with vehicle or increasing concentrations of compound C (10 or 40 mM) prior to overnight treatment+/−10 nM R1881 or 1 mM AICAR. Cells were then subjected to a migration assay as described in FIG. 7. The results are expressed as mean±SE (n=2). *, P<0.05 indicates significant changes from double vehicle-treated cells. #, P<0.05 indicates significant decreases from vehicle (no compound C)-treated cells. B, LNCaP cells were pretreated for 1 h with vehicle, 1, 10 or 40 mM compound C prior to overnight treatment+/−10 nM R1881. Cell lysates were then subjected to western blot analysis and subsequent densitometry (top). ACC is a direct target of AMPK and thus, was used as a readout of AMPK catalytic activity. Phospho-ACC (p-ACC) levels were normalized to total ACC. Results are expressed as fold induction/phosphorylation over double vehicle-treated cells+SE (n=2). *, P<0.05 indicates significant changes from double vehicle-treated cells. C, LNCaP cells were treated overnight+/−1 mM AICAR and then subjected to western blot analysis and densitometry (top) as in B. Phospho-AMPK (p-AMPK) levels were normalized to total AMPK. *, P<0.05 indicates significant changes from vehicle-treated cells.

DETAILED DESCRIPTION

The inventors have identified Ca2+/calmodulin-dependent protein kinase kinases (CaMKKs), such as CaMKKβ, as viable targets for therapeutic intervention in various cancers such as, for example, prostate cancer, glioblastoma, and myeloid leukemia as well as other cancer types described herein. In a general sense, the disclosure provides an array of compounds and compositions that are active inhibitors of CaMKK and use of such compounds in methods relating to detection, determination of disease stage/progression, prognostic evaluation of hormone therapy, treatment of disease, identification of active agents against various cancers, as well as identification of CaMKK inhibitors, including inhibitors that are selective for a particular CaMKK. For purposes of illustration some particular aspects and embodiments are explicitly described herein, relating to Ca2+/calmodulin-dependent protein kinase kinase β (CaMKKβ) which is shown (a) to be expressed in the prostate, (b) to be regulated by AR, (c) to correspond to prostate cancer progression/disease stage and, accordingly, provides a therapeutic target for prostate cancer.

As used herein, the term “Ca2+/calmodulin-dependent protein kinase kinase” and/or “CaMKK” are used interchangeably herein and refer to a serine/threonine protein kinase that can phosphorylate and activate members of the Ca2+/calmodulin-dependent protein kinase (CaMK) family of enzymes as well as other protein substrates such as AMPK (e.g., SEQ ID NOs: 21-24). The terms encompass all of the various isoforms, orthologs, and splice variants of CaMKK proteins such as, for example, Ca2+/calmodulin-dependent protein kinase kinase β (CaMKKβ, or CaMKK2) Ca2+/calmodulin-dependent protein kinase kinase α (CaMKKα, or CaMKK1), splice variants such as, for example, CaMKKβ splice variants 1-7, CaMKKα splice variants 1-3, and the like (e.g., SEQ ID NOs: 1-20 and 25-46). Some embodiments relate to CaMKKβ that comprises the amino acid sequence of SEQ ID NO:2, or a fragment thereof. The CaMKK amino acid sequences, such as CaMKKβ, can be encoded by any appropriate polynucleotide molecule as determined by the genetic code and codon usage in any particular organism. In embodiments, CaMKKβ is encoded by a polynucleotide comprising SEQ ID NO:1, or a fragment thereof. Some embodiments relate to CaMKKα that comprises the amino acid sequence of SEQ ID NO:16, or a fragment thereof. In some embodiments, CaMKKα like CaMKKβ above, is encoded by any polynucleotide that can be envisioned by one of skill in the art and, in some embodiments, comprises SEQ ID NO:15, or a fragment thereof.

In some embodiments the disclosure relates to a CaMKK splice variant. Non-limiting examples of CaMKK splice variants include nucleotide sequences of SEQ ID NOs: 3, 5, 7, 9, 11, 13, 17, and 19. Some embodiments relate to “CaMKKβ splice variant 2” and comprise a nucleotide sequence of SEQ ID NO:3, or a fragment thereof. Some embodiments relate to “CaMKKβ splice variant 7” and comprise a nucleotide sequence of SEQ ID NO: 13. In these embodiments, the splice variant proteins encoded by SEQ ID NO:3 and SEQ ID NO:13 are identical in sequence. Thus, embodiments of disclosure provide for a polynucleotide that encodes a CaMKKβ splice variant protein comprising SEQ ID NO:4, or a fragment thereof. Similarly, the disclosure relates to polynucleotide sequences that encodes an amino acid sequence of any CaMKK or CaMK protein such as, for example those of SEQ ID NOs: 2, 4, 6, 8, 10, 12, 14, 16, 18, or 20. As noted above, CaMKKβ splice variant 2 and splice variant 7 encode for the same amino acid sequence; thus, in embodiments relating to a CaMKKβ amino acid sequence encoded by splice variant 2 or splice variant 7, reference to an amino acid sequence encoded by either splice variant will also encompass the other (i.e., each term is interchangeable with and inclusive of the other when it relates to the encoded amino acid sequence).

Any sample can be used in the methods described herein. Embodiments provide for the use of a biological sample (e.g., tissue biopsy, cerebrospinal fluid, blood, sera, sputum, urine and/or tumor biopsies) from a subject with and/or without a cancer (which can be determined using standard clinical tests).

Embodiments of the disclosure relate to compounds that are inhibitors of a CaMK biochemical cascade. A CaMK biochemical cascade refers to a biochemical activation pathway that typically involves the phosphorylation of a first Ca2+/calmodulin-dependent protein kinase (CaMK) by a second Ca2+/calmodulin-dependent protein kinase (thus, a Ca2+/calmodulin-dependent protein kinase kinase (CaMKK)). The phosphorylated CaMK can subsequently phosphorylate a substrate. CaMK cascades are described in the literature. See, Corcoran, E. E., and Means, A. R., J Biol Chem, (Feb. 2, 2001); 276(5):2975-2978, incorporated herein by reference.

Methods of Treatment

In an aspect, the disclosure provides a method for treating cancer in a subject in need thereof comprising administering to the subject an effective amount of a Ca2+/calmodulin-dependent protein kinase kinase (CaMKK) inhibitor. In embodiments, the method comprises administering an effective amount of a CaMKK inhibitor that is a selective inhibitor of CaMKKα and/or CaMKKβ. In some embodiments the CaMKK inhibitor is a selective inhibitor of CaMKKα. In some embodiments the CaMKK inhibitor is a selective inhibitor of CaMKKβ. The term “selective inhibitor,” including “selective inhibitor of CaMKKβ/α” or “CaMKKβ/α selective inhibitor” relates to a compound (e.g., a small molecule or biological molecule) that has increased inhibitory activity for a target, for example, CaMKKβ or CaMKKα, relative to the inhibitory activity for other CaMKs. For purposes of illustration, when describing embodiments comprising a selective inhibitor of CaMKKβ, examples of “other” CaMKs include natural/physiological substrates of CaMKKβ such as, for example, Ca2+/calmodulin-dependent protein kinases (e.g., CaMKI and CaMKIV), CaMKs that are not substrates of CaMKKβ (e.g., CaMKII and CaMKIII), AMP-activated protein kinase (e.g., AMPKα1 subunit and AMPKα2 subunit) as well as other kinases that can phosphorylate such substrates (CaMKKα). Embodiments also relate to polypeptide fragments comprising a sequence that contains a portion of a CaMKKβ substrate. In such embodiments, the fragment comprises an amino acid that can be phosphorylated. In some embodiments a selective inhibitor comprises a ratio of IC50 concentrations (concentration inhibiting 50% of activity) wherein the ratio of the IC50 concentration for one or more other CaMKs to the IC50 concentration for CaMKKβ is greater than 1. The ratio of IC50 values can be readily determined from data obtained from one or more assay(s) (performed separately, in parallel or series) that is effective to measure activity or abundance of a CaMK or CaMKK (e.g., phosphorylation, mRNA transcription, protein expression, etc.), and can comprise any methods known in the art such as, for example those disclosed in U.S. Pat. No. 7,105,312, which is incorporated herein by reference. The inhibitory activity can be assessed and demonstrated either in vivo and/or in vitro optionally in cell-based or cell-free assay systems.

In general, the CaMKK inhibitor, including a CaMKK selective inhibitor, can be any type of chemical or biological molecule that exhibits inhibitory activity against one or more CaMKK. Effective CaMKK inhibitors for use in the methods described herein can inhibit the kinase activity of a CaMKK or they can regulate the amount of a CaMKK in a cell. Accordingly, the CaMKK inhibitors can inhibit phosphorylation associated with a CaMK cascade, and/or regulate expression of a CaMKK (e.g., by inhibiting a CaMKK gene promoter, inhibiting CaMKK gene transcription, inhibiting CaMKK mRNA translation, and/or affect CaMKK mRNA stability).

In some embodiments of this aspect, the method includes at least one selective inhibitor of CaMKKβ that comprises a compound of Formula III:

wherein R1, R2, R3, R4, R5, R6, R7, R7a, R8, R9, R10, and R11 are each independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkylalkynyl, heterocyclo, heterocycloalkyl, heterocycloalkenyl, heterocycloalkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, alkoxy, halo, mercapto, azido, cyano, formyl, carboxylic acid, hydroxyl, nitro, acyl, aryloxy, alkylthio, amino, alkylamino, arylalkylamino, disubstituted amino, acylamino, acyloxy, ester, amide, sulfoxyl, sulfonyl, sulfonate, sulfonic acid, sulfonamide, urea, alkoxylacylamino, aminoacyloxy, and, for the groups R7 and R7a, can optionally be taken together to form oxo; or a pharmaceutically acceptable salt or prodrug thereof. Such compounds are disclosed in U.S. patent application publication US 2010/0105716, incorporated herein by reference.

In further embodiments R7 and R7a together form oxo (C═O).

In some embodiments, R7 and R7a do not form oxo (C═O).

In some embodiments, R3 is —COOH, —CH2COOH, —CH2CH2COOH, or an ester thereof.

In some embodiments, R1, R2, R4, R5, R6, R7, R7a, R8, R9, R10, R11 are all H.

In some embodiments, at least one, two, or three of R1, R2, R4, R5, R6, R7, R7a, R8, R9, R10, and R11 is not H. Thus, in some embodiments, R1 is not H; in some embodiments R2 is not H; in some embodiments R3 is not H; in some embodiments R4 is not H; in some embodiments R5 is not H; in some embodiments R6 is not H; in some embodiments R7 is not H; in some embodiments R9 is not H; in some embodiments R10 is not H; and/or in some embodiments R11 is not H.

Compounds of Formula III, including further definitions of substituent terms and various formulations thereof are disclosed in U.S. Patent Application Publication No: 2010/0105716 as useful in methods of treating metabolic diseases/disorders including obesity, insulin resistance, hyperglycemia, diabetes, and the like. Synthetic routes and strategies for the compounds of Formula III are known in the art. The disclosure of US 2010/0105716 is incorporated herein by reference.

Embodiments of this aspect relate to a method comprising a selective inhibitor of CaMKKβ of Formula I:

wherein R1 is selected from CN, COOH, or COCl. Compounds of Formula I are described in U.S. Pat. No. 2,820,037 for use as dye molecules, and is incorporated herein by reference.

Other embodiments of this aspect relate to a method comprising a selective inhibitor of CaMKKβ of Formula II:

wherein R1 and R2 are independently selected from H, halo, alkyl, or haloalkyl; and R3 is H, alkyl, or substituted alkyl, or three COOR3 groups can be substituted at any location on the naphthalene ring. Compounds of Formula II are disclosed in Japanese Patent Application No. 2003-012516 as Ca2+/calmodulin dependent kinase kinase (CaMKK) inhibitors; however the reference fails to disclose the use of these compounds as effective in methods relating to cancer. The disclosure of Japanese Patent Application No. 2003-012516 is incorporated herein by reference.

The compounds of Formulas I-III can be synthesized by any method known in the art such as, for example, the methods described Japanese Patent Application No. 2003-012516; U.S. Pat. No. 2,820,037; U.S. Pat. No. 2,835,674; U.S. Pat. No. 2,965,644; U.S. Pat. No. 2,949,467; U.S. Pat. No. 3,953,452; U.S. Pat. No. 3,960,867; U.S. Pat. No. 4,239,868; and U.S. Pat. No. 4,336,383, each of which is incorporated herein by reference.

In other embodiments, the CaMKK inhibitor is a biological molecule, such as a polynucleotide having RNAi activity against a CaMKK or a substrate thereof, or an antibody that can specifically bind to a CaMKK or a substrate thereof.

Nucleic Acids/RNAi

Embodiments of the disclosure relate to methods that include CaMKK inhibitors, wherein the inhibitors comprise nucleic acid molecules having inhibitory activity against one or more biological molecules involved in a CaMK cascade including CaMK enzymes such as, for example, CaMKI and/or CaMKIV as well as kinases for such molecules (CaMKKα, CaMKKβ, etc.), other biological substrates of CaMKKs (e.g., AMPK), as well as other CaMKs (e.g., CaMKII and CaMKIII). In embodiments, the nucleic acid molecules can include decoy RNAs, dsRNAs, siRNAs, nucleic acid aptamers, antisense nucleic acid molecules, and enzymatic nucleic acid molecules that comprise a sequence that is sufficient allow for binding to a CaMK, AMPK, or CaMKK encoding nucleic acid sequence and inhibit activity thereof (i.e., are complementary to such encoding nucleic acid sequences).

In embodiments, the inhibitory nucleic acid molecule can bind to a target CaMK, AMPK, or CaMKK nucleic acid sequence under stringent binding conditions. The terms “stringent conditions”“stringent binding conditions” or “stringent hybridization conditions” refers to conditions under which a polynucleotide will hybridize to a target sequence, to a detectably greater degree than other sequences (e.g., at least 2-fold over background). An example of stringent conditions include those in which hybridization in 50% formamide, 1 M NaCl, 1% SDS at 37° C., and a wash in 0.1×SSC at 60° C. to 65° C. is performed. Amino acid and polynucleotide identity, homology and/or similarity can be determined using the ClustalW algorithm, MEGALIGN™ (Lasergene, Wis.).

Given a target polynucleotide sequence of a CaMK, CaMKK, or biological substrate thereof, an inhibitory nucleic acid molecule can be designed using motifs and targeted to a region that is anticipated to be effective for inhibitory activity, such as is known in the art.

Antibodies

Embodiments of the disclosure relate to methods that include CaMKK inhibitors, wherein the inhibitors comprise antibodies having specific binding activity against one or more biological molecules involved in a CaMK cascade including CaMK enzymes such as, for example, CaMKI and/or CaMKIV as well as kinases for such molecules (CaMKKα, CaMKKβ, etc.), biological substrates of CaMKKs (e.g., AMPK), and CaMKs that are not substrates of CaMKKs (e.g., CaMKII and CaMKIII).

Preparation of Antibodies

The antibodies described herein can be produced by any method known in the art, such as by immunization with a full-length CaMK or CaMKK, or fragments thereof. The antibodies can be polyclonal or monoclonal, and/or may be recombinant antibodies. In embodiments, antibodies that are human antibodies can be prepared, for example, by immunization of transgenic animals capable of producing a human antibody (see, for example, International Patent Application, Publication WO 93/12227).

Monoclonal antibodies (mAbs) can be produced by a variety of techniques, including conventional monoclonal antibody methodology, e.g., the standard somatic cell hybridization technique of Kohler and Milstein [Nature (1975); 256:495], and other techniques, e.g., viral or oncogenic transformation of B-lymphocytes.

Animal systems for preparing hybridomas include mouse. Hybridoma production in the mouse is very well established, and immunization protocols and techniques for isolation of immunized splenocytes for fusion are well known in the art. Fusion partners (e.g., murine myeloma cells) and fusion procedures are also known.

In embodiments, human monoclonal antibodies directed against a CaMK or CaMKK can be generated using transgenic mice carrying parts of the human immune system rather than the mouse system. These transgenic mice, referred to herein as “HuMab” mice, contain a human immunoglobulin gene minilocus that encodes unrearranged human heavy (μ and γ) and κ light chain immunoglobulin sequences, together with targeted mutations that inactivate the endogenous μ and κ chain loci [Lonberg et al., Nature (1994); 368:856-859]. The preparation of HuMab mice is described in detail in Taylor et al., Nucleic Acids Res. (1992); 20:6287-6295; Chen et al., International Immunology (1993); 5:647-656; Tuaillon et al., J. Immunol. (1994); 152:2912-2920; Lonberg et al., Nature (1994); 368:856-859; Lonberg, Handbook of Exp. Pharmacology (1994); 113:49-101; Taylor et al., International Immunology (1994); 6:579-591; Lonberg & Huszar, Intern. Rev. Immunol. (1995); 13:65-93; Harding & Lonberg, Ann. N.Y. Acad. Sci (1995); 764:536-546; Fishwild et al., Nature Biotechnology (1996); 14:845-851, the contents of all of which are hereby incorporated by reference in their entirety. See further U.S. Pat. Nos. 5,545,806; 5,569,825; 5,625,126; 5,633,425; 5,789,650; 5,877,397; 5,661,016; 5,814,318; 5,874,299; and 5,770,429; all to Lonberg and Kay, as well as U.S. Pat. No. 5,545,807 to Surani et al.; International Patent Application Publication Nos. WO 93/1227, published Jun. 24, 1993; WO 92/22646, published Dec. 23, 1992; and WO 92/03918, published Mar. 19, 1992, the disclosures of all of which are hereby incorporated by reference in their entirety.

Embodiments provide human monoclonal antibodies that are specific for and neutralize biological activity of human CaMK and/or CaMKK polypeptides. Such antibodies can comprise heavy and light chain amino acid sequences, the light and heavy chain variable regions, and any combination (including all) hypervariable CDR regions, which are specific for and neutralize CaMK and/or CaMKK polypeptides when they bind. Such antibodies can provide an effective immunotherapy for CaMK and CaMKK associated diseases including various cancers, such prostate cancer, glioma, glioblastoma, and myeloid leukemia. Such antibodies also provide a useful reagent for the detection of a CaMK or a CaMKK in a biological sample.

In an embodiment, the antibodies target an epitope in a region of CaMK and/or CaMKK located in the C-terminal portion. In some embodiments, the antibody recognizes and binds specifically to an epitope in the C-terminal region of CaMKKβ splice variants 2 and/or 7.

In some embodiments, the antibodies are of the IgG1, IgG2, IgG3, or IgG4 isotype. In other embodiments, the antibodies of the invention are of the IgM, IgA, IgE, or IgD isotype. In certain embodiments, the antibodies are cloned for expression in mammalian cells. In embodiments, the antibodies can be a fragment of an antibody that retains specific binding activity for a CaMK or CaMKK polypeptide and is effective to inhibit biological activity. Such fragments are known in the art and include, for example, single-chain antibodies (scFV), Fab, Fab′, Fab2, and the like.

Any of the CaMKK inhibitors disclosed herein and which are useful in the methods described herein can be provided as salts such as, for example, basic or acidic addition salts. The selection and formation of such salts are within the ability of one skilled in the art. See, e.g., Remington: The Science and Practice of Pharmacy, 21st ed., Lippincott Williams & Wilkins, A Wolters Kluwer Company, Philadelphia, Pa. (2005).

Further, embodiments of the disclosure provide for compositions or formulations comprising any of the CaMKK inhibitors disclosed herein that can are suitable for pharmaceutical use. Further, such formulations can be provided in suitable dosage forms. Such compositions, formulations, and dosage forms are known to those of skill in the art. For example, compounds of Formulas I-III can be provided as a composition or formulation and prepared in a dosage form as described U.S. patent application publication number US 2010/0105716, which is incorporated by reference herein. See, also, Remington: The Science and Practice of Pharmacy, 21st ed., Lippincott Williams & Wilkins, A Wolters Kluwer Company, Philadelphia, Pa. (2005).

In an aspect, the disclosure provides a method for screening or identifying a compound having agonist or antagonist activity for CaMKK (including CaMKKβ and/or CaMKKα) that includes contacting CaMKK and a substrate therefor, in the presence and absence of a test compound, under conditions that allow for CaMKK-dependent phosphorylation of the substrate; and determining, directly or indirectly, the level of phosphorylation of the substrate, wherein a reduction in phosphorylation of the substrate in the presence of the test compound is indicative of a CaMKK antagonist (for example, an anticancer agent) and an increase in phosphorylation of the substrate in the presence of the test compound is indicative of a CaMKK agonist. In embodiments, the CaMKK is CaMKKβ.

In some embodiments of this aspect, the method identifies a compound that is selective for a specific CaMK relative to at least one other CaMK. In further embodiments, the method identifies a compound that is selective for CaMKKβ relative to at least one other CaMK such as, for example, CaMKI, CaMKII, CaMKIII, CaMKIV, or CaMKKα. Yet further embodiments of the method provide identification of a compound that is selective for CaMKKβ splice variant 2 or CaMKKβ splice variant 7, relative to at least one other CaMKKβ isoform, and relative to at least one other CaMK such as, for example, CaMKI, CaMKII, CaMKIII, CaMKIV, or CaMKKα.

Embodiments of these methods provide compounds having selective antagonist activity for a CaMK wherein the CaMK-dependent phosphorylation of the substrate is reduced by about 4-fold or more in the presence of the compound compared to phosphorylation in the absence of the compound (e.g., about 4-fold to about 100-fold or more).

Merely for purposes of illustration of an embodiment of this aspect, an assay system can comprise calmodulin (CaM), calcium, CaMKKβ, and a substrate (such as a synthetic peptide that can be phosphorylated by CaMKKβ such as from either AMPK or CaMKIV). The assay can further comprise evaluation of the test compound(s) that involves AMPK as the enzyme and a peptide from acetyl-CoA-carboxylase (ACC) as the substrate. In particular, assay conditions that allow for phosphorylation are provided (e.g., any appropriate buffer system) and further includes one or the other of CaMKKα and CaMKKβ (i.e., run in parallel), a calcium salt (e.g., CaCl2), a phosphate source (e.g., ATP, optionally comprising radiolabelled 32P), calmodulin (CaM, e.g., from bovine), and two substrates (one that can be phosphorylated by both CaMKKα and CaMKKβ, while the other can only be phosphorylated by one or the other of CaMKKα or CaMKKβ). A non-limiting example of a substrate that can be phosphorylated by both CaMKKα and CaMKKβ includes CaMIV, or a peptide fragment thereof (for example, Lys-Lys-Lys-Lys-Glu-His-Gln-Val-Leu-Met-Lys-Thr-Val-Cys-Gly-Thr-Pro-Gly-Tyr). A non-limiting example of a substrate that can be phosphorylated by CaMKKβ and not CaMKKα includes AMPK, or a peptide fragment thereof (for example, Ala-Lys-Pro-Lys-Gly-Asn-Lys-Asp-Tyr-His-Leu-Gln-Thr-Cys-Cys-Gly-Ser-Leu-Ala-Tyr-Arg-Arg-Arg). Any substrate, including fragments thereof can be used in these methods, as long as the substrate can be phosphorylated. Differences between the amount of phosphorylation of the substrates can be used to evaluate the substrate specificity and selectivity of a candidate test compound. Concentrations of the various assay components can vary widely, but are usually in the range of 1 nM to 500 μM (for active reagents including proteins and substrates, phosphate source(s) and test compounds) and in the mM range for other assay components (calcium and magnesium salts/cofactors, reducing agents, buffer systems, etc.). Incubation time and temperature can also be varied depending on the particular activity and sensitivity of the assay components. In embodiments, the temperature can range from about 4° C. to about 30° C., and the incubation time can be on the order of minutes (e.g., 10 minutes) to hours (e.g., 1 hrs, 1.5 hrs, 2 hrs, 2.5 hrs, 3 hrs, 3.5 hrs, etc.). In embodiments, a selective inhibitor will inhibit CaMKKβ activity to a greater extent than it will inhibit CaMKKα activity. In some embodiments the selective inhibitor will inhibit CaMKKβ activity about anywhere from about 3-100 fold or more, relative to CaMKKα activity (e.g., about 10-20 fold, about 20-30 fold, about 40-50 fold, about 50-60 fold, about 60-70 fold, about 70-80 fold, about 80-90 fold, about 90-100 fold, or over 100 fold).

Embodiments of the disclosure provide for detection of CaMKK, such as CaMKKβ and/or CaMKKα in circulating tumor cells (CTCs). CTCs are known in the art and comprise cells that have detached from a primary tumor and circulate in the bloodstream. It is thought that CTCs may indicate potential for metastasis and spread of a primary tumor to different tissues. Thus, circulating tumor cells can be a factor indicating the metastatic spread of cancers, such as carcinomas, and can be used in methods for the detection of, and prognosticate the likelihood of, metastatic disease. See, e.g., Fidler I. J., Nat Rev Cancer (2003); 3:453-8; Sleijfer S., et al., Eur J Cancer (2007); 43:2645-50; Hayes D. F., and Smerage J., Clin Cancer Res (2008); 14:3646-50; Pantel K, et al., Nat Rev Clin Oncol (2009); 6:339-51; Pantel K., and Riethdorf S., Nat Rev Clin Oncol. (2009); 6:190-1; and Panteleakou Z., et al., Mol Med (2009); 15:101-14, all incorporated by reference. Methods for expanding and enriching the number of CTCs in a biological sample are known in the art and allow for measurable amounts of a biochemical marker (a genetic or biochemical signature, such as CaMKKβ) of disease (e.g., an androgen-driven cancer). Accordingly, methods for detecting the presence of a CaMK, such as CaMKKβ/α or phosphorylated AMPK allow for identification of therapies that can be useful in treatment of disease. In embodiments, such methods provide for a method of monitoring the course of a therapeutic treatment, such as administering an inhibitor of CaMKKβ, in a patient undergoing therapy, based on a detectable increase or decrease in the amount of the biochemical marker(s) in a sample comprising CTCs. Such analytic methods include Kaplan Meier Analysis which has been used to correlate overall survival before starting a new line of therapy for patients with metastatic breast, colorectal and prostate cancer. Patients can be divided into those with Favorable and Unfavorable CTC (Unfavorable: >5 CTC/7.5 mL for breast and prostate, >3 CTC/7.5 mL for colon). See, Miller, M. C., et al., J of Oncology. 2010. doi:10.1155/2010/617421. incorporated by reference. Methods known in the art, such as the CellSearch system (“Veridex CellSearch Website”. March 2010. http://veridex.com/CellSearch/CellSearchHCP.aspx. Retrieved Mar. 14, 2010), as well as other methods, have been demonstrated as a strong prognostic factor for overall survival in patients with metastatic breast, colorectal or prostate cancer. See, e.g., Paterlini-Brechot P, and Benali N. L., Cancer Lett. (2007); 253:180-204; “Veridex LLC. CellSearch circulating tumor cell kit premarket notification—expanded indications for use—metastatic prostate cancer”. March 2010. http://www.fda.gov/cdrh/pdf7/K073338.pdf. Retrieved Mar. 14, 2010; Cristofanilli M., et al., NEJM (2004); 351:781-91; Budd G., et al., Clin Can Res (2006); 12:6404-09; Cohen, S. J., et al., JCO (2008); 26:3213-21; DeBono, J. S., et al., Clin Can Res (2008); 14:6302-9; Allard, W. J., et al., Clin Can Res (2004); 10:6897-6904; and Riethdorf et al., Clin Cancer Res (2007); 13:920-8, all incorporated by reference.

In an aspect, the disclosure also provides a method for treating conditions or diseases associated with abnormal AMP-activated protein kinase (AMPK) activity, which includes increased phosphorylation of AMPK, by administering an effective amount of at least one compound that inhibits CaMKKβ to a subject having such a condition or disease. Diseases characterized by abnormal AMPK activity include, but are not limited to, various cancers including prostate cancer.

As used herein, the term “subject” is intended to include human and non-human animals. Exemplary human subjects include a human patient having a disorder, e.g., a disorder described herein, such as cancer, or a normal subject. The term “non-human animals” includes all vertebrates, e.g., non-mammals (such as chickens, amphibians, reptiles) and mammals, such as non-human primates, domesticated and/or agriculturally useful animals (such as sheep, dogs, cats, cows, pigs, etc.), and rodents (such as mice, rats, hamsters, guinea pigs, etc.).

“Treatment” or “treat” refers to both therapeutic treatment and prophylactic or preventative measures. Those subjects in need of treatment include those already with the disorder as well as those prone to have the disorder or those in which the disorder is to be prevented.

The terms “treating” and “treatment” refer to both therapeutic treatment and prophylactic or preventative measures. Those subjects in need of treatment include those already with the disorder as well as those prone to have the disorder or those in which the disorder is to be prevented. When used with reference to a disease or a subject in need of treatment the terms accordingly include, but are not limited to, halting or slowing of disease progression, remission of disease, prophylaxis of symptoms, reduction in disease and/or symptom severity, or reduction in disease length as compared to an untreated subject. In embodiments, the methods of treatment can abate one or more clinical indications of the particular disease being treated. Certain embodiments relating to methods of treating a disease or condition associated with activation of a substrate in a CaMK cascade (CaMKI, CaMKIV, AMPK) and comprise administration of therapeutically effective amounts of a compound that inhibits CaMKKβ, as well as pharmaceutical compositions thereof. In embodiments, the method of treating can relate to any method that prevents further progression of the disease and/or symptoms, slows or reduces the further progression of the disease and/or symptoms, or reverses the disease and/or clinical symptoms associated with expression of CaMKKβ or kinase activity thereof.

In embodiments, the methods are used to treat cancer in a subject, wherein the subject is a mammal. Yet further embodiments relate to methods wherein the mammal is a human.

Aspects of the disclosure provide a method of inhibiting CaMKKβ in a cell, including a cell within a subject, comprising contacting the cell with a compound in an amount effective to inhibit CaMKKβ activity. In embodiments, the method provides for inhibiting CaMKKβ activity in a cell in a subject, wherein the method includes administering to the subject a compound, or a pharmaceutically acceptable salt thereof, according to Formula I in an amount effective to inhibit CaMKKβ activity in the cell in the subject. Both the activity of CaMKKβ and AMPK can be monitored by any method familiar to those of skill in the art. In some embodiments CaMKKβ and/or AMPK activity can be monitored by clinical evaluation of the symptoms or stage of a disease associated with abnormal CaMKKβ and/or AMPK activity. In embodiments, the disease is cancer. In further embodiments, the cancer is glioma, glioblastoma, carcinoma, or leukemia. In some embodiments, the cancer is prostate cancer, cancer of the blood or bone marrow, or cancer of the brain/CNS.

In these embodiments, “inhibiting” or “inhibition” of CaMKKβ means that there is a measurable decrease in the activity of CaMKKβ in the presence of a compound (e.g., through contacting/administration), relative to the activity of CaMKKβ in the absence of the compound. As described above, the decrease in CaMKKβ activity can arise from direct inhibition of kinase activity by, for example, binding of a small molecule inhibitor of Formulas I-III to the active site of CaMKKβ. A decrease in CaMKKβ activity can also arise from inhibition of expression of a CaMKKβ gene via antisense inhibition, gene silencing, disruption or degradation of CaMKKβ mRNA via RNAi (e.g., siRNA). CaMKKβ expression can also be modulated indirectly by manipulating the activity or expression of a regulator of CaMKKβ, such as androgen receptor (AR) or proteins involved in CaMKKβ splicing activity such as Fox2/RTA-1, using any agent having such activity. In embodiments, CaMKKβ can be inhibited by about 10% to about 100% or more (e.g., about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 200%, 300%, 500%, etc.) relative to a control. In some embodiments compounds can inhibit CaMKKβ (e.g., IC50) at concentrations from about 0.1 nM to about 500 μM, (e.g., about 0.1 nM to about 250 μM, about 0.5 nM to about 200 μM, about 1.0 nM to about 100 μM, about 10 nM to about 50 μM, or about 100 nM to about 10 μM, and the like).

In some embodiments the therapeutically effective amount is an amount sufficient to stop or slow the progression of the cancer. In further embodiments, the therapeutically effective amount is an amount sufficient to reduce the number of cancer cells in the subject (i.e., killing of cancer cells). Methods for monitoring the proliferation of cancer cells and progress of cancer in a subject (e.g., tumor size, cell counts, biochemical markers, secondary indications, etc.) are known in the art.

In various embodiments of the method, the cancer is associated with the activity of CaMKKβ. Non-limiting examples of cancer that are associated with CaMKKβ activity include carcinoma, melanoma, leukemia, myeloid leukemia, glioma, and glioblastoma. In embodiments, the cancer is leukemia, cancer of the prostate or cancer of the brain/central nervous system. In further embodiments, the cancer is prostate cancer.

In some embodiments, the method of treatment is used as a co-therapy such as, for example, administration in conjunction with radiation, surgery, or other chemotherapeutics. In some embodiments, the method includes administration of a therapeutically effective amount of a compound that inhibits CaMKKβ in combination with an additional anti-cancer agent. A wide variety of anti-cancer (i.e., anti-neoplastic) agents are known in the art and include, for example alkylating agents, antimetabolites, natural antineoplastic agents, hormonal antineoplastic agents, angiogenesis inhibitors, differentiating reagents, RNA inhibitors, antibodies or immunotherapeutic agents, gene therapy agents, small molecule enzymatic inhibitors, biological response modifiers, and anti-metastatic agents.

In embodiments, the method comprises treating prostate cancer in a subject who is in need of treatment, where the method includes administering to the subject an effective amount of a CaMKK inhibitor in combination with a second treatment. In such embodiments, the second treatment can include such non-limiting examples as surgery, radiation, and chemotherapy. In further embodiments, the method comprises co-administration of an effective amount of a CaMKK inhibitor and a second agent effective against prostate cancer such as, for example, anti-androgens, Selective Androgen Receptor Modulators (SARMs), Selective Androgen Receptor Degraders (SARDs), CYP17 inhibitors, suphatase inhibitors, Src inhibitors, anti-estrogens, estrogens, Selective Estrogen Receptor Modulators (SERMs), Selective Estrogen Receptor Degraders (SERDs), ERb antagonists, aromatase inhibitors, vaccine-based therapeutics such as sipuleucel-T (Provenge®), and the like. In further embodiments the method comprises administration an effective amount of a CaMKK inhibitor and an active agent selected from MDV3100 (an androgen receptor antagonist from Medivation Inc., San Francisco, Calif.); ARN-509 (an androgen receptor antagonist from Aragon Pharmaceuticals, San Diego, Calif.); bicalutamide (Casodex® a non-steroidal anti-androgen from AstraZeneca); or flutamide (Eulexin® a non-steroidal anti-androgen from Schering-Plough).

In some embodiments, the method of treatment can be used an adjuvant therapy (i.e., additional treatment) such as, for example, when compounds of any of Formulas I-III, or pharmaceutical compositions thereof, are administered after surgery or other treatments (e.g., radiation, hormone therapy, or chemotherapy). Accordingly, in such embodiments, the method of adjuvant therapy encompasses administering the compounds of Formula I-III to a subject following a primary or initial treatment, and can be administered either alone or in combination with one or more other adjuvant treatments, including, for example surgery, radiation therapy, or systemic therapy (e.g., chemotherapy, immunotherapy, hormone therapy, or biological response modifiers). Those of skill in the art will be able to use statistical evidence to assess the risk of disease relapse before deciding on the specific adjuvant therapy. The aim of adjuvant treatment is to improve disease-specific and overall survival. Because the treatment is essentially for a risk, rather than for provable disease, it is accepted that a proportion of patients who receive adjuvant therapy will already have been effectively treated or cured by their primary surgery. Adjuvant therapy is often given following surgery for many types of cancer including, for example, colon cancer, lung cancer, pancreatic cancer, breast cancer, prostate cancer, and some gynecological cancers.

Some embodiments of the method relate to neoadjuvant therapy, which is administered prior to a primary treatment. Effective neoadjuvant therapy is commonly characterized by a reduction in the number of cancer cells (e.g., size of the tumor) so as to facilitate more effective primary treatment such as, for example, surgery.

The term “cancer” refers to or describes the physiological condition in mammals that is typically characterized by unregulated cell growth. Some non-limiting examples of cancer include carcinoma, melanoma, lymphoma, blastoma, sarcoma, germ cell tumors, and leukemia or lymphoid malignancies. Non-limiting examples of cancers that fall within these broad categories include squamous cell cancer (e.g., epithelial squamous cell cancer), lung cancer including small-cell lung cancer, non-small cell lung cancer, adenocarcinoma of the lung and squamous carcinoma of the lung, cancer of the peritoneum, hepatocellular cancer, gastric or stomach cancer including gastrointestinal cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, cancer of the urinary tract, hepatoma, breast cancer, colon cancer, rectal cancer, colorectal cancer, endometrial or uterine carcinoma, salivary gland carcinoma, kidney or renal cancer, prostate cancer, vulval cancer, thyroid cancer, hepatic carcinoma, anal carcinoma, melanoma, multiple myeloma and B-cell lymphoma, brain, as well as head and neck cancer, and associated metastases.

The term “cancer” also encompasses cell proliferative disorders which are associated with some degree of abnormal cell proliferation, and includes tumors. “Tumor” as used herein, refers to any neoplasm or neoplastic cell growth and proliferation, whether malignant or benign, and all pre-cancerous and cancerous cells and tissues. In embodiments disclosed above, the cancer can be prostate cancer, cancer of the brain/CNS (glioma, glioblastoma, etc.), or leukemia (myeloid leukemia).

Administration of an effective amount of an inhibitor of CaMKK such as, for example a compound of Formula I-III, such as STO-609 for example, to a subject may be carried out by any means known in the art including, but not limited to intraperitoneal, intravenous, intramuscular, subcutaneous, or transcutaneous injection or oral, nasopharyngeal or transmucosal absorption. Such administration encompasses the administration of a CaMKK inhibitor formulated as a pharmaceutical composition. Delivery (administration route) also includes targeted delivery wherein the CaMKK inhibitor is only active in a targeted region of the body (for example, in the prostate and/or cancerous tissues), as well as sustained release formulations in which the CaMKK inhibitor compound is released over a period of time in a controlled manner. Sustained release formulations and methods for targeted delivery are known in the art and include, for example, use of liposomes, drug loaded biodegradable microspheres, drug-polymer conjugates, drug-specific binding agent conjugates and the like. Pharmaceutically acceptable carriers are well known to those of skill in the art. Determination of particular pharmaceutical formulations and therapeutically effective amounts and dosing regimen for a given treatment is within the ability of one of skill in the art taking into consideration, for example, patient age, weight, sex, ethnicity, organ (e.g., liver and kidney) function, the extent of desired treatment, the stage and severity of the disease and associated symptoms, and the tolerance of the patient for the treatment.

Kits

In an aspect, the disclosure relates to kits. Such kits can be used in methods of identifying a cancer that can be responsive to a method of treatment comprising administration of a CaMKK inhibitor, methods of identifying a compound as an inhibitor of CaMKK, methods of evaluating efficacy of a therapeutic regimen comprising administration of a CaMKK inhibitor, and the like. Kits can also include appropriate buffer systems and reagents, such as substrates of one or more CaMKKs, phosphate-donating groups (optionally radiolabelled phosphate-donating groups such as 32P-ATP), a calmodulin and a calcium source, typically a calcium salt, and molecules that can detect the presence of a CaMK or CaMKK (e.g., antibodies). Kits also include instructions for use.

It will be understood that any numerical value recited herein includes all values from the lower value to the upper value. For example, if a concentration range is stated as 1% to 50%, it is intended that values such as 2% to 40%, 10% to 30%, or 1% to 3%, etc., are expressly enumerated in this specification. These are only examples of what is specifically intended, and all possible combinations of numerical values between the lowest value and the highest value enumerated are to be considered to be expressly stated in this application.

Also, it is to be understood that the phraseology and terminology used herein is for the purpose of description and should not be regarded as limiting. The use herein of terms such as “comprising,”“including,”“having,” and variations thereof is meant to encompass the items listed thereafter and equivalents thereof as well as additional items. “Comprising” encompasses the terms “consisting of” and “consisting essentially of.” The use of “consisting essentially of” means that the composition or method may include additional ingredients and/or steps, but only if the additional ingredients and/or steps do not materially alter the basic and novel characteristics of the claimed composition or method.

All patents publications and references cited herein are hereby fully incorporated by reference.

While the following examples provide further detailed description of certain embodiments of the invention, they should be considered merely illustrative and not in any way limiting the invention, as defined by the claims.

EXAMPLES

Materials and Methods.

Cell culture and RNA. The LNCaP and VCaP human prostate carcinoma cell lines were obtained from ATCC and maintained as recommended. All experiments were performed with cells of passage less than 25. These cells were authenticated by morphological inspection and mycoplasma testing by the ATCC. Furthermore, their response to androgens was authenticated using growth and reporter gene assays. RNA from placenta, skeletal muscle, cerebellum, whole brain and normal prostate was from Clontech (Mountain View, Calif.). RNA from glioblastoma cell lines was a generous gift from Valerie Curtis (Duke University, Durham, N.C.).

RNA isolation, cDNA preparation, and quantitative and standard reverse transcription (RT)-PCR. RNA isolation, cDNA preparation and quantitative RT-PCR (qPCR) were performed as previously described using 36B4 as a control (12). Standard RT-PCR was performed using the Advantage GC 2 Polymerase Mix and PCR Kit (Clontech). All qPCR and RT-PCR primers used in this study are listed in Table 1.

Western blot analysis. Western blots were performed as previously described (12) with the exception that a modified radioimmunoprecipitation assay (RIPA) buffer [50 mM Tris (pH 8.0), 200 mM NaCl, 1.5 mM MgCl2, 1% Triton X-100, 1 mM EGTA, 10% glycerol, 50 mM NaF, 2 mM Na3VO4 and protease inhibitors] was used. Results shown are representative blots. For each sample, protein levels were determined by densitometry using the ImageJ software (NIH) and normalizing to indicated controls.

Small interfering RNA (siRNA) transfection of human prostate cells. Stealth siRNA (Invitrogen) transfections were performed as previously described (5). The sequences of all siRNAs used in this study are listed in Table 1.

Chromatin immunoprecipitation (ChIP). ChIP was performed as previously described (4). All primers used for ChIP qPCR analysis are listed in Table 1.

Transient transfections and reporter gene assays. Transient transfections and reporter gene assays were performed as previously described (4).

Cell proliferation assay. Proliferation assays were performed as previously described (12) by measuring the cellular DNA content using the FluoReporter Blue Fluorometric double-stranded DNA Quantitation Kit (Invitrogen) as per the manufacturer's protocol.

Migration and invasion assays. Boyden dual chamber migration assays were performed as previously described (4). Invasion assays were performed the same as migration assays except that inserts were layered with 100 ml of Matrigel extracellular matrix (BD Biosciences) prior to reseeding of cells.

Statistical analysis. Data were analyzed using one-way ANOVA and post hoc Dunnett's test with GraphPad Prism, Version 4 (GraphPad Software, Inc.). Unless otherwise noted, significance was determined at the P<0.05 level.

Chemicals. Methyltrienolone (R1881) was purchased from PerkinElmer (Waltham, Mass.) and dissolved in ethanol. Bicalutamide (Casodex) was provided as a gift from P. Turnbull (GlaxoSmithKline, Research Triangle Park, N.C.) and resuspended in a 1:1 mixture of ethanol and dimethylsulfoxide (DMSO). Cycloheximide was obtained from Sigma (St Louis, Mo.) and dissolved in DMSO. Compound C (in DMSO) was from Calbiochem (San Diego, Calif.). STO-609 was purchased from Tocris (Ellisville, Mo.) and resuspended in 100 mM NaOH. 5-aminoimidazole-4-carboxamide 1-b-D-ribo-furanoside (AICAR) was from Enzo Life Sciences (Plymouth Meeting, Pa.) and dissolved in water.

Antibodies. The CaMKK antibody used, unless otherwise specified, was from BD Biosciences (Palo Alto, Calif.). The CaMKKβ (clone 1A11) antibody was from Abnova (Walnut, Calif.). The v5 antibody was purchased from Invitrogen (Carlsbad, Calif.). The GAPDH and AR antibodies have previously been described (1). Phospho-CaMKI (T177), CaMKI and Lamin A antibodies were from Santa Cruz Biotechnology, Inc. (Santa Cruz, Calif.). Phospho-AMPKa (T172), AMPKa, phospho-acetyl-CoA carboxylase (S79), and acetyl-CoA carboxylase antibodies were from Cell Signaling Technology (Danvers, Mass.).

Plasmids. The CMV-βgal and PSA-Luc plasmids were previously described (2). The pGL4.14 (lacks both basal promoter and enhancers) and pGL4.26 (lacks enhancer, but contains basal promoter) vectors were obtained from Promega (Madison, Wis.). MSCV-GWb-GAL4(DNA-binding domain (DBD))-IRES-EGFP, MSCV-GWb-CaMKKβ-IRES-EGFP, MSCV-GWb-v5-ARwt-IRES-EGFP and MSCV-GWb-v5-AR(C562S)-IRES-EGFP were created using the Invitrogen Gateway recombinase subcloning system according to the manufacturer's instructions. To do this, GAL4(DBD), CaMKKβ, v5-ARwt or v5-AR(C562S) were shuttled from pENTR-GAL4(DBD), pENTR-v5-ARwt, pENTR-v5-AR(C562) or pOTB7-CaMKKβ□□prostate splice variant□ (American Type Culture Collection (ATCC), Manassas, Va.) to MSCV-IRES-EGFP that was converted to a Gateway destination vector. The pGL4.14-CaMKKβ promoter construct was created by PCR amplifying a 2.1 kb genomic sequence that encompassed the CaMKKβ transcriptional start site through the potential AR binding site identified using ChIP on Chip (previously described (3)). This fragment was then cloned into the pGL4.14 vector using NheI and HindIII restriction sites. Subsequent deletion constructs were created by PCR amplifying smaller fragments that were cloned into pGL4.26 using NheI and HindIII restriction sites. Finally, the pGL4.14-CaMKKβ promoter-ARE deletion construct was created from the original pGL4.14-CaMKKβ promoter construct using the ExSite PCR-Based Site-Directed Mutagenesis Kit (Stratagene, La Jolla, Calif.). All primers used for the creation of constructs are listed in Supplementary Table 1. All sequences were confirmed using restriction digests and sequencing.

Creation of stable cell lines. To create LNCaP-GAL4, LNCaP-CAMKKβ□□LNCaP-v5-ARwt and LNCaP-v5-AR(C562S) cells, parental cells were infected with retrovirus expressing MSCV-GWb-GAL4(DBD)-IRES-EGFP (negative control), MSCV-GWb-CAMKKβ-IRES-EGFP, MSCV-GWb-v5-ARwt-IRES-EGFP or MSCV-GWb-v5-AR(C562S)-IRES-EGFP. EGFP positive cells were then selected through two rounds of cells sorting using flow cytometry and expression levels were confirmed by western blot and/or qPCR.


TABLE 1
Primers and siRNA sequences used in these studies
Primer/siRNA
Sequence (SEQ ID NO)
qPCR primers
36B4
Forward: 5′-GGACATGTTGCTGGCCAATAA-3′
(SEQ ID NO: 48)
Reverse: 5′-GGGCCCGAGACCAGTGTT-3′
(SEQ ID NO: 49)
CaMKKβ
Forward: 5′-TCCAGACCAGCCCGACATAG-3′
(SEQ ID NO: 50)
Reverse: 5′-CAGGGGTGCAGCTTGATTTC-3′
(SEQ ID NO: 51)
CXCR4
Forward: 5′-TGGCCTTATCCTGCCTGGTAT-3′
(SEQ ID NO: 52)
Reverse: 5′-AGGAGTCGATGCTGATCCCAA-3′
(SEQ ID NO: 53)
AR 3′UTR
Forward: 5′-CCATGGCACCTTCAGACTTT-3′
(SEQ ID NO: 54)
Reverse: 5′-ACTGGGCCATATGAGGATCA-3′
(SEQ ID NO: 55)
AMPKα1
Forward: 5′-CTCAGTTCCTGGAGAAAGATGG-3′
(SEQ ID NO: 56)
Reverse: 5′-CCCAGTCAATTCATGTTTGCC-3′
(SEQ ID NO: 57)
AMPKα2
Forward: 5′-ATGGAATATGTGTCTGGAGGTG-3′
(SEQ ID NO: 58)
Reverse: 5′-TGGTTTCAGGTCTCGATGAAC-3′
(SEQ ID NO: 59)
CaMKKβ 
enhancer
ChIP primers
distal  
Forward: 5′-GCACAGTTTGCACACCTGAA-3′
upstream
(SEQ ID NO: 60)
control
Reverse: 5′-GCTTTGGATTTAGGCCCTGT-3′
(SEQ ID NO: 61)
CaMKKβ
Forward: 5′-AACAGGAAAGGACACCCAAA-3′
enhancer
(SEQ ID NO: 62)
Reverse: 5′-AAACCATTCTTAGCAGGCCAT-3′
(SEQ ID NO: 63)
CaMKKβ
enhancer
and promoter
reporter 
gene
primers
promoter
Fwd: 
5′-CGCTAGCAGGGAGGTGGCTGAGCATCAAATA-3′
(SEQ ID NO: 64)
Rv: 
5′-CAAAGCTTTGAGACAGGGTCTCTCTGTGTTGC-3′
(SEQ ID NO: 65)
fragment A 
Fwd: 
enhancer
5′-CGCTAGCGAATTGCAACTGTGAGACCAGGCA-3′
(SEQ ID NO: 66)
Rv: 
5′-CAAAGCTTGTGGCCTTGGGCAAATGACTTGAT-3′
(SEQ ID NO: 67)
fragment B 
Fwd: 
enhancer
5′-CGCTAGCATCAAGTCATTTGCCCAAGGCCAC-3′
(SEQ ID NO: 68)
Rv: 
5′-CAAAGCTTAACACTGTAGCTCACACAGGCAGA-3′
(SEQ ID NO: 69)
fmgment C 
Fwd: 
enhancer
5′-CGCTAGCATCAAGTCATTTGCCCAAGGCCAC-3′
(SEQ ID NO: 70)
Rv: 
5′-CAAAGCTTTATTTGATGCTCAGCCACCTCCCT-3′
(SEQ ID NO: 71)
fragment  
Fwd: 
D/598
5′-CGCTAGCAGGGAGGTGGCTGAGCATCAAATA-3′
bp enhancer
(SEQ ID NO: 72)
Rv: 
5′-CAAAGCTTAAATGTGAAAGGCCAGGTGTGGTG-3′
(SEQ ID NO: 73)
fragment E 
Fwd: 
enhancer
5′-CGCTAGCTGCCTGTGTGAGCTACAGTGTTCT-3′
(SEQ ID NO: 74)
Rv: 
5′-CAAAGCTTAAATGTGAAAGGCCAGGTGTGGTG-3′
(SEQ ID NO: 75)
fragment F 
Fwd: 
enhancer
5′-CGCTAGCAGGGAGGTGGCTGAGCATCAAATA-3′
(SEQ ID NO: 76)
Rv: 
5′-CAAAGCTTAACACTGTAGCTCACACAGGCAGA-3′
(SEQ ID NO: 77)
fragment G 
Fwd: 
enhancer
5′-CGCTAGCCACCACACCTGGCCTTTCACATTT-3′
(SEQ ID NO: 78)
Rv: 
5′-CAAAGCTTGCACTTTAAGGCAGGGTCAGCAAA-3′
(SEQ ID NO: 79)
fragment H 
Fwd: 
enhancer
5′-CGCTAGCGTTTCAAGCGATTCTCCTGCCTCA-3′
(SEQ ID NO: 80)
Rv: 
5′-CAAAGCTTTCACGCCTGTAATCCCAGCACTTT-3′
(SEQ ID NO: 81)
566 bp 
Fwd: 
enhancer
5′-CGCTAGCAGGGAGGTGGCTGAGCATCAAATA-3′
(SEQ ID NO: 82)
Rv: 
5′-CAAAGCTTTACACGGGTGATTACAATCTTAGC-3′
(SEQ ID NO: 83)
487 bp 
Fwd: 
enhancer
5′-CGCTAGCAGGGAGGTGGCTGAGCATCAAATA-3′
(SEQ ID NO: 84)
Rv: 
5′-CAAAGCTTTGGACAACATGGCAAGACCCATCT-3′
(SEQ ID NO: 85)
312 bp 
Fwd: 
enhancer
5′-CGCTAGCAGGGAGGTGGCTGAGCATCAAATA-3′
(SEQ ID NO: 86)
Rv: 
5′-CAAAGCTTCTGGATCTCTTTTCCTGGTACTTG-3′
(SEQ ID NO: 87)
233 bp 
Fwd: 
enhancer
5′-CGCTAGCAGGGAGGTGGCTGAGCATCAAATA-3′
(SEQ ID NO: 88)
Rv: 
5′-CAAAGCTTACACTGTAGCTCACACAGGCAGAA-3′
(SEQ ID NO: 89)
152 bp 
Fwd: 
enhancer
5′-CGCTAGCAGGGAGGTGGCTGAGCATCAAATA-3′
(SEQ ID NO: 90)
Rv: 
5′-CAAAGCTTTACAAATCCAAACCCTAGCTCAAG-3′
(SEQ ID NO: 91)
 90 bp 
Fwd: 
enhancer
5′-CGCTAGCAGGGAGGTGGCTGAGCATCAAATA-3′
(SEQ ID NO: 92)
Rv: 
5′-CAAAGCTTTGCTGTGAGCCAGGCCCTCCCTGC-3′
(SEQ ID NO: 93)
 69 bp 
Fwd: 5
enhancer
′-CGCTAGCAGGGAGGTGGCTGAGCATCAAATA-3′
(SEQ ID NO: 94)
Rv: 
5′-CAAAGCTTCTGCCCGCTCCTCTCTCTGATGTC-3′
(SEQ ID NO: 95)
promoter- 
Forward: 
ARE
5′-CATACAGAATTGTTTAACAAGTACC-3′
deletion
(SEQ ID NO: 96)
Rv: 
5′-TAAATTGCCTGTGTTTTATTAGAACACTG-3′
(SEQ ID NO: 97)
CaMKKβ RT-
PCR primers
F(1-6)
5′-ACCTGTAATCCCAGCACTTTCGGA-3′
(SEQ ID NO: 98)
R(1-6)
5′-CGATCTCGGATCACTGCAACCTCT-3′
(SEQ ID NO: 99)
F(7)
5′-TGAGCCGAGCCGAGCCGAGCTG-3′
(SEQ ID NO: 100)
R(1-7)
5′-TCACAGGGCTTCTGGCTTTCGCT-3′
(SEQ ID NO: 101)
F1
5′-AGCTGAGGACTTGAAGGACCTGAT-3′
(SEQ ID NO: 102)
R1
5′-AGGTTGTCTTCGCTGCCTTGCTT-3′
(SEQ ID NO: 103)
R2
5′-ACCTGGGCTGGCTATGTGTATGAA-3′
(SEQ ID NO: 104)
siRNA 
sequences
CaMKKβ #1
5′-GGACCAUCUGUACAUGGUGUUCGAA-3′
(SEQ ID NO: 105)
CaMKKβ #2
5′-GCUGACUUUGGUGUGAGCAAUGAAU-3′
(SEQ ID NO: 106)
CaMKKβ #3
5′-CACCUGGGCAUGGAGUCCUUCAUUG-3′
(SEQ ID NO: 107)
AR 3′UTR
5′-CAGAUGUCUUCUGCCUGUUAUAACU-3′
(SEQ ID NO: 108)
AMPKα1 #1
5′-CCCAUCCUGAAAGAGUACCAUUCUU-3′
(SEQ ID NO: 109)
AMPKα1 #2
5′-CCCUCAAUAUUUAAAUCCUUCUGUG-3′
(SEQ ID NO: 110)
AMPKα1 #3
5′-ACCAUGAUUGAUGAUGAAGCCUUAA-3′
(SEQ ID NO: 111)
AMPKα2 #1
5′-GAUGGUGAAUUUCUGAGAACUAGUU-3′
(SEQ ID NO: 112)
AMPKα2 #2
5′-CCGUAUGACAUUAUGGCUGAAGUUU-3′
(SEQ ID NO: 113)
CaMKI #1
5′-GGAGATACAGCTCTAGATAAGAATA-3′
(SEQ ID NO: 114)
CaMKI #2
5′-CCATAGGTGTCATCGCCTACATCTT-3′
(SEQ ID NO: 115)

Example 1: Androgens Increase CaMKKβ mRNA and Protein Levels in an AR-Dependent Manner

In an effort to identify novel prostate cancer therapeutics, we have focused on defining key regulators downstream of AR action that contribute to prostate pathobiology and that may be amenable to pharmacological exploitation. As a first step in this process, we analyzed the expression level of mRNAs encoding targetable signaling molecules using microarray data derived from androgen-treated LNCaP prostate cancer cells (13). These studies suggested that one such candidate, CaMKKβ, was upregulated by androgens. To confirm the significance of this observation, CaMKKβ mRNA levels were analyzed by qPCR following treatment with the synthetic androgen R1881. In both LNCaP and VCaP prostate cancer cell lines, CaMKKβ mRNA levels increased in a dose-dependent manner (FIG. 1A). Further, western immunoblot analysis revealed a corresponding dose-dependent increase in CaMKKβ protein levels in both cell lines (FIG. 1B). The specificity of the antibodies used in this study was verified using three siRNAs targeting CaMKKβ mRNA (FIG. 1C). In addition, analogous immunoblot results were obtained using a second antibody (clone 1A11) directed against CaMKKβ (FIG. 2). Finally, androgen-mediated induction, but not the basal expression, of CaMKKβ mRNA was abrogated in cells in which AR expression was inhibited using a validated siRNA (4) directed against the AR mRNA (FIG. 1D). Taken together, these data demonstrate that androgens, acting through AR, increase both CaMKKβ mRNA and protein levels in multiple cellular models of prostate cancer.

Example 2: Functionally Active Splice Variants of CaMKKβ are Expressed in Response to Androgens in the Prostate

Given that AR increases CaMKKβ levels in multiple cellular models of prostate cancer, we next determined if its expression correlated with the development of prostate cancer in human samples. Analysis of the clinically annotated prostate cancer data sets accessible through Oncomine revealed that CaMKKβ expression increases with grade (14-17) (FIG. 3A and FIG. 3B). Interestingly, this analysis also revealed that CaMKKβ was consistently overexpressed in prostate tumors, but not other malignancies (FIG. 3C) (18).

The full-length CaMKKβ protein is encoded by an mRNA composed of 18 exons. Interestingly, the majority of commercially available CaMKKβ antibodies target the C-terminus of the protein that is absent in some functionally active splice variants (19). Thus, given that the expression of CaMKKβ in the prostate has not been reported previously, we hypothesized that the prostate, and prostate cancers, may express a functionally important splice variant(s) of CaMKKβ that was not recognized by the most commonly used antibodies. To test this hypothesis, we performed RT-PCR analysis using primers spanning various exon boundaries to examine the splice variant repertoire in the normal prostate and in prostate cancer cells. In this manner, it was demonstrated that unlike in brain, which expresses a longer variant, both normal prostate and prostate cancer cells predominantly express shorter variants of CaMKKβ (FIG. 4A, FIG. 4B, and FIG. 5). The variants found are equivalent to the previously described CaMKKβ splice variants 2 and 7 that lack exon 16 (of note, splice variants 2 and 7 make identical protein products) (19). Interestingly, these shorter variants were also found in brain tumors (FIG. 4B). A complete analysis of the additional variants expressed in the prostate/prostate cancer is described in FIG. 5. Phosphorylation of the classical CaMKKβ target CaMKI was observed in both androgen-treated LNCaP and VCaP cells (FIG. 4C), indicating that the CaMKKβ variant expressed in prostate cancer cells is functionally active.

Example 3: CaMKKβ is Necessary and Sufficient for AR-Mediated Prostate Cancer Cell Migration and Invasion

Given that the expression of CaMKKβ is upregulated by androgens and is elevated in prostate cancer, we next wanted to assess its potential role(s) in processes of pathological importance in this disease. As a first step, we evaluated the ability of the CaMKK antagonist STO-609 to inhibit the androgen-mediated cellular growth of prostate cancer cells. However, at a concentration that suppressed CaMKKβ activity (FIG. 6A), this drug had no significant effect on LNCaP and VCaP cell number over the seven-day period of this assay (FIG. 7A and FIG. 6B).

In addition to proliferation, androgens increase the migration of prostate cancer cells (4, 20). Since CaMKKβ has recently been implicated in cell migration during neuronal development (21, 22), we next asked whether CaMKKβ is involved with AR-meditated prostate cancer cell migration and/or invasion. Using Boyden dual chamber migration assays, treatment with the CaMKK antagonist STO-609 blocked the androgen-mediated migration of both LNCaP (FIG. 7B, top) and VCaP prostate cancer cells (FIG. 6C). STO-609 also inhibited androgen-mediated invasion of LNCaP cells through a Matrigel extracellular matrix (FIG. 7B, bottom). Furthermore, knockdown of CaMKKβ suppressed, while its overexpression increased, both basal and androgen-stimulated cell migration (FIG. 7C, FIG. 7D, FIG. 6D, and FIG. 6E). These findings highlight a heretofore-unrecognized role for CaMKKβ in prostate cancer cell migration and invasion.

Example 4: Definition of the Molecular Mechanism for AR-Mediated CaMKKβ mRNA Expression

Using a knockdown/replacement strategy, it was demonstrated that expression of wild-type AR, but not a transcriptionally inactive DNA binding mutant (C562S), was able to complement the knockdown of endogenously expressed AR in an LNCaP cell migration assay (FIG. 8). Further, at a concentration that inhibits the expression of secondary androgen target genes (ex. CXCR4 (4)), cycloheximide treatment did not block the R1881-mediated increase in CaMKKβ mRNA levels (FIG. 9A). Together, these data indicate that CaMKKβ is a primary AR target gene.

By mining our previously published ChIP on Chip data (23), we identified a putative AR binding region located ˜2.3 kb upstream of the CaMKKβ transcriptional start site (FIG. 9B, top). No other AR binding was detected within the CaMKKβ gene or within 100 kb in either direction of the gene. The validity of this AR-binding site was confirmed using ChIP assays, which showed that AR was recruited to this region of the promoter within one hour following R1881 treatment (FIG. 9B, bottom). Given these data, we focused on characterizing the functionality of the putative ARE identified. To this end, we cloned overlapping regions of CaMKKβ's 5′ upstream region and tested their ability to confer androgen responsiveness to an enhancerless luciferase reporter gene. In this manner, we determined that a construct incorporating a fragment, −2231 to −1632 (D), and an overlapping fragment, −2019 to −1632 (E), contained an AR-dependent enhancer (FIG. 9C). Both fragments D and E demonstrated androgen responsiveness in a dose-dependent manner that was suppressed by the antiandrogen Casodex (FIG. 10A). Similar results were obtained in VCaP cells (FIG. 10B). Deletion analysis further narrowed down the androgen-responsive region to a 79 bp stretch of DNA that included a sequence, GTAACAtgaTGTAAA, that resembled the consensus androgen response element (ARE) AGAACAnnnTGTTCT (FIG. 10C). Deletion of the 15 bp ARE in the full-length CaMKKβ promoter construct (−2231 to +83) completely abolished the androgen responsiveness (FIG. 9D). Thus, in the context of prostate cancer cells, CaMKKβ is a direct target of AR.

Example 5: Androgens Promote Prostate Cancer Cell Migration Through an AR-CaMKKβ-AMPK Signaling Axis

CaMKI, CaMKIV and, more recently, AMPK have been shown to be downstream targets of CaMKKβ (24). Since CaMKIV is not expressed in the prostate (data not shown), we tested whether AR-CaMKKβ signaling led to increased CaMKI and/or AMPK signaling. Western blot analysis revealed that androgens increased the phosphorylation of both CaMKI and AMPK at their CaMKKβ activation loop target sites (T177 and T172 respectively) in both LNCaP and VCaP cells, an effect that was reversed by pretreatment with STO-609 (FIG. 11A and FIG. 12A). Interestingly, we found that overexpression of CaMKKβ alone was sufficient to increase the phosphorylation/activity of AMPK, but not CaMKI (FIG. 11B). These findings indicated that AMPK, rather than CaMKI, could be regulating cell migration because CaMKKβ overexpression alone was also sufficient to increase migration (FIG. 7D). To verify this, we used our most efficacious siRNAs (FIG. 12B) to knockdown both isoforms of the catalytic subunit of AMPK (FIG. 11C, bottom and FIG. 12C) or CaMKI (FIG. 11D, bottom and FIG. 12D). In this manner, it was demonstrated that loss of AMPK, but not CaMKI, resulted in decreased prostate cancer cell migration (FIG. 11C and FIG. 11D). In support of these findings, cotreatment of cells with the AMPK antagonist compound C, at a concentration that inhibited its kinase activity, completely abolished androgen-mediated cell migration (FIG. 13A and FIG. 13B). Conversely, treatment of LNCaP cells with the AMP mimetic AICAR alone was sufficient to increase cell migration (FIG. 13A and FIG. 13C). These data highlight a central role for AMPK in prostate cancer cell migration. Definition of the mechanism(s) by which AMPK interfaces with the cellular processes responsible for migration and invasion is currently under investigation.

REFERENCES

The following references are incorporated herein by reference in their entireties.

  • 1. Cancer Facts and Figures: American Cancer Society; 2007.
  • 2. Isaacs J T, Isaacs W B. Androgen receptor outwits prostate cancer drugs. Nat Med 2004; 10: 26-7.
  • 3. Chen C D, Welsbie D S, Tran C, et al. Molecular determinants of resistance to antiandrogen therapy. Nature Med 2004; 10: 33-9.
  • 4. Frigo D E, Sherk A B, Wittmann B M, et al. Induction of Kruppel-like factor 5 expression by androgens results in increased CXCR4-dependent migration of prostate cancer cells in vitro. Mol Endocrinol 2009.
  • 5. Sherk A B, Frigo D E, Schnackenberg C G, et al. Development of a small molecule serum and glucocorticoid-regulated kinase 1 antagonist and its evaluation as a prostate cancer therapeutic. Cancer Res 2008; 68: 1-9.
  • 6. Xu Y, Chen S Y, Ross K N, Balk S P. Androgens induce prostate cancer cell proliferation through mammalian target of rapamycin activation and post-transcriptional increases in cyclin D proteins. Cancer Res 2006; 66: 7783-92.
  • 7. Migita T, Ruiz S, Fornari A, et al. Fatty acid synthase: a metabolic enzyme and candidate oncogene in prostate cancer. J Natl Cancer Inst 2009; 101: 519-32.
  • 8. Balk S P, Knudsen K E. AR, the cell cycle, and prostate cancer. Nucl Recept Signal 2008; 6: e001.
  • 9. Lawton C A, Winter K, Murray K, et al. Updated results of the phase III radiation therapy oncology group (RTOG) trial 85-31 evaluating the potential benefit of androgen suppression following standard radiation therapy for unfavorable prognosis carcinoma of the prostate. Int J Radiation Oncology Biol Phys 2001; 49: 937-46.
  • 10. Bolla M, Collette L, Blank L, et al. Long-term results with immediate androgen suppression and external irradiation in patients with locally advanced prostate cancer (an EORTC study): a phase III randomised trial. The Lancet 2002; 360: 103-8.
  • 11. Scher H I, Beer T M, Higano C S, et al. Antitumour activity of MDV3100 in castration-resistant prostate cancer: a phase 1-2 study. Lancet; 375: 1437-46.
  • 12. Frigo D E, McDonnell D P. Differential effects of prostate cancer therapeutics on neuroendocrine transdifferentiation. Mol Cancer Ther 2008; 7: 659-69.
  • 13. Kazmin D, Prytkova T, Cook C E, et al. Linking ligand-induced alterations in androgen receptor structure to differential gene expression: a first step in the rational design of selective androgen receptor modulators. Mol Endocrinol 2006; 20: 1201-17.
  • 14. Lapointe J, Li C, Higgins J P, et al. Gene expression profiling identifies clinically relevant subtypes of prostate cancer. Proc Natl Acad Sci USA 2004; 101: 811-6.
  • 15. Varambally S, Yu J, Laxman B, et al. Integrative genomic and proteomic analysis of prostate cancer reveals signatures of metastatic progression. Cancer Cell 2005; 8: 393-406.
  • 16. Welsh J B, Sapinoso L M, Su A T, et al. Analysis of gene expression identifies candidate markers and pharmacological targets in prostate cancer. Cancer Res 2001; 61: 5974-8.
  • 17. Yu Y P, Landsittel D, Jing L, et al. Gene expression alterations in prostate cancer predicting tumor aggression and preceding development of malignancy. J Clin Oncol 2004; 22: 2790-9.
  • 18. Su A T, Welsh J B, Sapinoso L M, et al. Molecular classification of human carcinomas by use of gene expression signatures. Cancer Res 2001; 61: 7388-93.
  • 19. Hsu L S, Chen G D, Lee L S, Chi C W, Cheng J F, Chen J Y. Human Ca2+/calmodulin-dependent protein kinase kinase beta gene encodes multiple isoforms that display distinct kinase activity. J Biol Chem 2001; 276: 31113-23.
  • 20. Liao X, Thrasher J B, Pelling J, Holzbeierlein J, Sang Q X, Li B. Androgen stimulates matrix metalloproteinase-2 expression in human prostate cancer. Endocrinology 2003; 144: 1656-63.
  • 21. Kokubo M, Nishio M, Ribar T J, Anderson K A, West A E, Means A R. BDNF-mediated cerebellar granule cell development is impaired in mice null for CaMKK2 or CaMKIV. J Neurosci 2009; 29: 8901-13.
  • 22. Saneyoshi T, Wayman G, Fortin D, et al. Activity-dependent synaptogenesis: regulation by a CaM-kinase kinase/CaM-kinase I/betaPIX signaling complex. Neuron 2008; 57: 94-107.
  • 23. Wang Q, Li W, Zhang Y, et al. Androgen receptor regulates a distinct transcription program in androgen-independent prostate cancer. Cell 2009; 138: 245-56.
  • 24. Means A R. The Year in Basic Science: calmodulin kinase cascades. Mol Endocrinol 2008; 22: 2759-65.
  • 25. Attar R M, Takimoto C H, Gottardis M M. Castration-resistant prostate cancer: locking up the molecular escape routes. Clin Cancer Res 2009; 15: 3251-5.
  • 26. Wayman G A, Lee Y S, Tokumitsu H, Silva A, Soderling T R. Calmodulin-kinases: modulators of neuronal development and plasticity. Neuron 2008; 59: 914-31.
  • 27. Hawley S A, Pan D A, Mustard K J, et al. Calmodulin-dependent protein kinase kinase-beta is an alternative upstream kinase for AMP-activated protein kinase. Cell Metab 2005; 2: 9-19.
  • 28. Woods A, Dickerson K, Heath R, et al. Ca2+/calmodulin-dependent protein kinase kinase-beta acts upstream of AMP-activated protein kinase in mammalian cells. Cell Metab 2005; 2: 21-33.
  • 29. Hurley R L, Anderson K A, Franzone J M, Kemp B E, Means A R, Witters L A. The Ca2+/calmodulin-dependent protein kinase kinases are AMP-activated protein kinase kinases. J Biol Chem 2005; 280: 29060-6.
  • 30. Salt I, Celler J W, Hawley S A, et al. AMP-activated protein kinase: greater AMP dependence, and preferential nuclear localization, of complexes containing the alpha2 isoform. Biochem J 1998; 334 (Pt 1): 177-87.
  • 31. Berglund L, Bjorling E, Oksvold P, et al. A genecentric Human Protein Atlas for expression profiles based on antibodies. Mol Cell Proteomics 2008; 7: 2019-27.
  • 32. Park H U, Suy S, Danner M, et al. AMP-activated protein kinase promotes human prostate cancer cell growth and survival. Mol Cancer Ther 2009; 8: 733-41.
  • 33. Zhou J, Huang W, Tao R, et al. Inactivation of AMPK alters gene expression and promotes growth of prostate cancer cells. Oncogene 2009; 28: 1993-2002.
  • 34. Ben Sahra I, Laurent K, Loubat A, et al. The antidiabetic drug metformin exerts an antitumoral effect in vitro and in vivo through a decrease of cyclin D1 level. Oncogene 2008; 27: 3576-86.
  • 35. Xiang X, Saha A K, Wen R, Ruderman N B, Luo Z. AMP-activated protein kinase activators can inhibit the growth of prostate cancer cells by multiple mechanisms. Biochem Biophys Res Commun 2004; 321: 161-7.
  • 36. Nagata D, Mogi M, Walsh K. AMP-activated protein kinase (AMPK) signaling in endothelial cells is essential for angiogenesis in response to hypoxic stress. J Biol Chem 2003; 278: 31000-6.
  • 37. Levine Y C, Li G K, Michel T. Agonist-modulated regulation of AMP-activated protein kinase (AMPK) in endothelial cells. Evidence for an AMPK→Rac1→Akt→endothelial nitric-oxide synthase pathway. J Biol Chem 2007; 282: 20351-64.
  • 38. Kou R, Sartoretto J, Michel T. Regulation of Rac1 by simvastatin in endothelial cells: differential roles of AMP-activated protein kinase and calmodulin-dependent kinase kinase-beta. J Biol Chem 2009; 284: 14734-43.
  • 39. Jaffe A B, Hall A. Rho GTPases: biochemistry and biology. Annu Rev Cell Dev Biol 2005; 21: 247-69.
  • 40. Knight-Krajewski S, Welsh C F, Liu Y, et al. Deregulation of the Rho GTPase, Rac1, suppresses cyclin-dependent kinase inhibitor p21(CIP1) levels in androgen-independent human prostate cancer cells. Oncogene 2004; 23: 5513-22.
  • 41. Kobayashi T, Inoue T, Shimizu Y, et al. Activation of Rac1 is closely related to androgen-independent cell proliferation of prostate cancer cells both in vitro and in vivo. Mol Endocrinol 2010; 24: 722-34.
  • 42. Butler L M, Wong A S, Koh W P, Wang R, Yuan J M, Yu M C. Calcium intake increases risk of prostate cancer among Singapore Chinese. Cancer Res 2010; 70: 4941-8.
  • 43. Yang S, Zhang J J, Huang X Y. Orai1 and STIM1 are critical for breast tumor cell migration and metastasis. Cancer Cell 2009; 15: 124-34.
  • 44. Monet M, Lehen'kyi V, Gackiere F, et al. Role of cationic channel TRPV2 in promoting prostate cancer migration and progression to androgen resistance. Cancer Res 2010; 70: 1225-35.
  • 45. Kampa M, Papakonstanti E A, Alexaki V I, Hatzoglou A, Stournaras C, Castanas E. The opioid agonist ethylketocyclazocine reverts the rapid, non-genomic effects of membrane testosterone receptors in the human prostate LNCaP cell line. Exp Cell Res 2004; 294: 434-45.
  • 46. Papakonstanti E A, Kampa M, Castanas E, Stournaras C. A rapid, nongenomic, signaling pathway regulates the actin reorganization induced by activation of membrane testosterone receptors. Mol Endocrinol 2003; 17: 870-81.
  • 47. Wang Q, Li W, Liu X S, et al. A hierarchical network of transcription factors governs androgen receptor-dependent prostate cancer growth. Mol Cell 2007; 27: 380-92.

<160> NUMBER OF SEQ ID NOS: 119

<210> SEQ ID NO: 1

<211> LENGTH: 5620

<212> TYPE: DNA

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic

<400> SEQENCE: 1

gagcctgggg aggtcgaggg tgcagcgagc cgtgatcgtg ctactgcact ccagcctggg 60

caacacagag agaccctgtc tcaaaacaaa caaacaaaca aacaaacaaa caaacaaaaa 120

aaacaaagaa aaaaaaatgg gagtgggccg ggcgcggtga ctcacacctg taatcccagc 180

actttcggag gccaaggcgg gtggatcacg aggtcaggaa ttcaagatta gcctggacaa 240

catggtgaaa ccccatctct acgaaaaata caaaaattag ccaagtatgg tggccggcgc 300

ctgtaatccc agctactcgg gagactgagg cagagaactg cttgaacctg ggaggcagag 360

gttgcagtga tccgagatcg cgtcactgca ctccagcgtg ggcgacagag cgagactccg 420

tttcagaaaa gaaaaaaaaa aaaaaaaaaa agggagtcgg ggtggagctc tcattggctc 480

gttgcatgtg agtgtcccta cggcctagaa atacaagaga agcacatcgg aacgggctgg 540

aaatccaccc agttaactag agggctttga accttttatt aacttggagg ttgactctcc 600

tgtcaactcg attccctttt ggctgtttgg cagggtcagt gagacatccc ctgggtcgct 660

cgaccccgta ggacggttca gggagccctc caggtcttcg tttctcctct tccccgcaca 720

gtgctgttat ccagctgggg gatccaacgc acacttaagg ctccagcaaa gtggctccgc 780

tgccggatgg gagtgcccca gtgtgctgga tgaagctggc gcatgcacca tgtcatcatg 840

tgtctctagc cagcccagca gcaaccgggc cgccccccag gatgagctgg ggggcagggg 900

cagcagcagc agcgaaagcc agaagccctg tgaggccctg cggggcctct catccttgag 960

catccacctg ggcatggagt ccttcattgt ggtcaccgag tgtgagccgg gctgtgctgt 1020

ggacctcggc ttggcgcggg accggcccct ggaggccgat ggccaagagg tcccccttga 1080

cacctccggg tcccaggccc ggccccacct ctccggtcgc aagctgtctc tgcaagagcg 1140

gtcccagggt gggctggcag ccggtggcag cctggacatg aacggacgct gcatctgccc 1200

gtccctgccc tactcacccg tcagctcccc gcagtcctcg cctcggctgc cccggcggcc 1260

gacagtggag tctcaccacg tctccatcac gggtatgcag gactgtgtgc agctgaatca 1320

gtataccctg aaggatgaaa ttggaaaggg ctcctatggt gtcgtcaagt tggcctacaa 1380

tgaaaatgac aatacctact atgcaatgaa ggtgctgtcc aaaaagaagc tgatccggca 1440

ggccggcttt ccacgtcgcc ctccaccccg aggcacccgg ccagctcctg gaggctgcat 1500

ccagcccagg ggccccattg agcaggtgta ccaggaaatt gccatcctca agaagctgga 1560

ccaccccaat gtggtgaagc tggtggaggt cctggatgac cccaatgagg accatctgta 1620

catggtgttc gaactggtca accaagggcc cgtgatggaa gtgcccaccc tcaaaccact 1680

ctctgaagac caggcccgtt tctacttcca ggatctgatc aaaggcatcg agtacttaca 1740

ctaccagaag atcatccacc gtgacatcaa accttccaac ctcctggtcg gagaagatgg 1800

gcacatcaag atcgctgact ttggtgtgag caatgaattc aagggcagtg acgcgctcct 1860

ctccaacacc gtgggcacgc ccgccttcat ggcacccgag tcgctctctg agacccgcaa 1920

gatcttctct gggaaggcct tggatgtttg ggccatgggt gtgacactat actgctttgt 1980

ctttggccag tgcccattca tggacgagcg gatcatgtgt ttacacagta agatcaagag 2040

tcaggccctg gaatttccag accagcccga catagctgag gacttgaagg acctgatcac 2100

ccgtatgctg gacaagaacc ccgagtcgag gatcgtggtg ccggaaatca agctgcaccc 2160

ctgggtcacg aggcatgggg cggagccgtt gccgtcggag gatgagaact gcacgctggt 2220

cgaagtgact gaagaggagg tcgagaactc agtcaaacac attcccagct tggcaaccgt 2280

gatcctggtg aagaccatga tacgtaaacg ctcctttggg aacccattcg agggcagccg 2340

gcgggaggaa cgctcactgt cagcgcctgg aaacttgctc accaaaaaac caaccaggga 2400

atgtgagtcc ctgtctgagc tcaaggaagc aaggcagcga agacaacctc cagggcaccg 2460

acccgccccc cgtgggggag gaggaagtgc tcttgtgaga ggcagtccct gcgtggaaag 2520

ttgctgggcc cccgcccccg gctcccccgc acgcatgcat ccactgcggc cggaggaggc 2580

catggagccc gagtagctgc ctggatcgct cgacctcgca tgcgcgccgc gtcgcctctg 2640

gggggctgct gcaccgcgtt tccatagcag catgtcctac ggaaacccag cacgtgtgta 2700

gagcctcgat cgtcatctct ggttatttgt tttttccttt gttgttttaa aggggacaaa 2760

aaaaaaaaaa ggacttgact ccatgacgtc gaccgtggcc gctggctggc tggacaggcg 2820

ggtgtgagga gttgcagacc caaacccacg tgcattttgg gacaattgct ttttaaaacg 2880

tttttatgcc aaaaatcctt cattgtgatt ttcagaacca cgtcagatat accaagtgac 2940

tgtgtgtggg gtttgacaac tgtggaaagg cgagcagaaa actccggcgg tctgaggcca 3000

tggaggtggt tgctgcattt gagagggagt agggggctag atgtggctcc tagtgcaaac 3060

cggaaaccat ggcaccttcc agagccgtgg tctcaaggag tcagagcagg gctggccctc 3120

agtagctgca gggagctttg atgcaactta tttgtaagaa ggatttttaa attttttatg 3180

ggtagaattg tagtcaggaa aacagaaagg gcttgaaatt taataagtgc tgctggaagg 3240

ggattttcca agcctggaag ggtattcagc agctgtggtg gggaaacatt tctcctgaaa 3300

gactgaacgt gtttcttcat gacagctgct caaagcaggt ttctgagata gctgaccgag 3360

ctctggtaaa tctctttgtc aaattacgaa aacttcaggg tgaaatccta tgcttccatg 3420

tacattacat ggcttaagat taaacaaaaa catttttcaa gtctctaact agagtgaact 3480

ctagagcaca gtagttcaga aactatttag agcttccagg atatatttca cagcttcagg 3540

catgtgatca gttagagccg atgaaaccta tgcccgcctg tatatatatt agcagcttag 3600

ctagttcata acctgtatat tctaaagact gctaaggttt tgttttcatt ttaaatccta 3660

gctgattgtt gtggtcaatg aaatacccag tttctggagg gccaggtggg aaatgctttc 3720

actggaccaa cacacaaatg atcatcctga ggatctgagc ttccctagac tccacacaat 3780

aaccttgggg caccctttta gagaagactg ttgaaaccca cagcactcgt tggggtatga 3840

ggaaaccagg gcttggcaca ggaagttccc ctttgtagct aaaagtccag aaagaaaggg 3900

ttcatctttt tgacttccaa ctgatattgg gaagtttggt tgaggttcaa gtgtgactcc 3960

ttccagagcc acaggtaggg gagtgtgaag ttgaggggga ggaaagctgg aaggactctg 4020

ccttgggaga ttcccagctc tgctttccag cgcttggtgg aatctgggct ggggaaagac 4080

ggcaccggga aactctgctt ccccattgtt tccatctgat cagctgtggt gtgaggactt 4140

ctcagacaaa ggcaaggcct cgtgcccctg cccagcccat tcatggagcc ctgggccttc 4200

ttggcttcca tagatcctaa gctcttgact gtagtttagc cagacttgtt ttgctatctt 4260

ataagcagtt cagaattagg gaatgctggt tttgaagagc aaaggacagg tagtctagag 4320

agggtcgtct ggcctgcttg ctgggtcttt gtaacccagc acttcctctt gccctcctgg 4380

ctttatgttt atggggagag gactcaatag ctccacccct tctggcacca gatggggctt 4440

ggttagtttg caataagcac cttgcagagg ttaaagccag cgggtcccta gtcttaggcc 4500

cagcctgctt gtgtgggctc tggcctggcc tggtggctgg cccagggggc agcagtgctt 4560

agagcttctg cagggcttct cttgtttaca cagctgcatc agacaatgcc atttctcccc 4620

accacggaac cttccatcta agatttcttc cagggaatgc cagcaatcag gcagcaccca 4680

gctgtggggg cagtggggtg ggggagaccc acattgatga cttttttttt ttcttttaat 4740

gaagaaacac caaagaaagc tgtggaaagg acctgcccca catgaaaagg ataagccaag 4800

atggctgtaa acacagagca tttgagctgc cactcttgga gcacattgat ttttcaaaag 4860

ccagctctgt caggaaagga ggtgctgtta tgagcagctc ttccagtggg caaagaggac 4920

gcccataatt tcttccattg ctagctcatc tgtgggacca atttggtgta agcaacctgt 4980

ggcctgcact tgtggcctcg aaggaagcac aaaccctcca tccacttccc atttcctctg 5040

cccttttcca cctccccctt ccatcccacc agctgccagt ggctcccaga aagccttatt 5100

gagccccttg ttgacacttg gggctgcgga ggcctctccc tactggtctg gcctttcctg 5160

agaggcaggt cttccgtcct cagagccttt ctggaacaag gagaatgcct gtgcaggtgg 5220

acacacaggc ctggcctgtc gctctcactt gtcttccagc ggggagcttc acgttgccga 5280

gtggaagaac catgacctcc acttgcttcc aaggtgctag ggaagtttca gggtacgctg 5340

gttcccctct ccagctggag gccgagtttc tggggactgc agatttttct actctgtgat 5400

cgattcaatg cccgatgctt ctgtttcatt cccgaccctt tctactatgc attttccttt 5460

tatcaggtgt ataaagttaa atactgtgta tttatcacta aaaagtacat gaacttaaga 5520

gacaactaag cctttcgtgt ttttccacag gtgtttaagc ttctctgtac agttgaaata 5580

aacagacagc aaaatggtgc caaaaaaaaa aaaaaaaaaa 5620

<210> SEQ ID NO: 2

<211> LENGTH: 588

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic

<400> SEQENCE: 2

Met Ser Ser Cys Val Ser Ser Gln Pro Ser Ser Asn Arg Ala Ala Pro

1 5 10 15

Gln Asp Glu Leu Gly Gly Arg Gly Ser Ser Ser Ser Glu Ser Gln Lys

20 25 30

Pro Cys Glu Ala Leu Arg Gly Leu Ser Ser Leu Ser Ile His Leu Gly

35 40 45

Met Glu Ser Phe Ile Val Val Thr Glu Cys Glu Pro Gly Cys Ala Val

50 55 60

Asp Leu Gly Leu Ala Arg Asp Arg Pro Leu Glu Ala Asp Gly Gln Glu

65 70 75 80

Val Pro Leu Asp Thr Ser Gly Ser Gln Ala Arg Pro His Leu Ser Gly

85 90 95

Arg Lys Leu Ser Leu Gln Glu Arg Ser Gln Gly Gly Leu Ala Ala Gly

100 105 110

Gly Ser Leu Asp Met Asn Gly Arg Cys Ile Cys Pro Ser Leu Pro Tyr

115 120 125

Ser Pro Val Ser Ser Pro Gln Ser Ser Pro Arg Leu Pro Arg Arg Pro

130 135 140

Thr Val Glu Ser His His Val Ser Ile Thr Gly Met Gln Asp Cys Val

145 150 155 160

Gln Leu Asn Gln Tyr Thr Leu Lys Asp Glu Ile Gly Lys Gly Ser Tyr

165 170 175

Gly Val Val Lys Leu Ala Tyr Asn Glu Asn Asp Asn Thr Tyr Tyr Ala

180 185 190

Met Lys Val Leu Ser Lys Lys Lys Leu Ile Arg Gln Ala Gly Phe Pro

195 200 205

Arg Arg Pro Pro Pro Arg Gly Thr Arg Pro Ala Pro Gly Gly Cys Ile

210 215 220

Gln Pro Arg Gly Pro Ile Glu Gln Val Tyr Gln Glu Ile Ala Ile Leu

225 230 235 240

Lys Lys Leu Asp His Pro Asn Val Val Lys Leu Val Glu Val Leu Asp

245 250 255

Asp Pro Asn Glu Asp His Leu Tyr Met Val Phe Glu Leu Val Asn Gln

260 265 270

Gly Pro Val Met Glu Val Pro Thr Leu Lys Pro Leu Ser Glu Asp Gln

275 280 285

Ala Arg Phe Tyr Phe Gln Asp Leu Ile Lys Gly Ile Glu Tyr Leu His

290 295 300

Tyr Gln Lys Ile Ile His Arg Asp Ile Lys Pro Ser Asn Leu Leu Val

305 310 315 320

Gly Glu Asp Gly His Ile Lys Ile Ala Asp Phe Gly Val Ser Asn Glu

325 330 335

Phe Lys Gly Ser Asp Ala Leu Leu Ser Asn Thr Val Gly Thr Pro Ala

340 345 350

Phe Met Ala Pro Glu Ser Leu Ser Glu Thr Arg Lys Ile Phe Ser Gly

355 360 365

Lys Ala Leu Asp Val Trp Ala Met Gly Val Thr Leu Tyr Cys Phe Val

370 375 380

Phe Gly Gln Cys Pro Phe Met Asp Glu Arg Ile Met Cys Leu His Ser

385 390 395 400

Lys Ile Lys Ser Gln Ala Leu Glu Phe Pro Asp Gln Pro Asp Ile Ala

405 410 415

Glu Asp Leu Lys Asp Leu Ile Thr Arg Met Leu Asp Lys Asn Pro Glu

420 425 430

Ser Arg Ile Val Val Pro Glu Ile Lys Leu His Pro Trp Val Thr Arg

435 440 445

His Gly Ala Glu Pro Leu Pro Ser Glu Asp Glu Asn Cys Thr Leu Val

450 455 460

Glu Val Thr Glu Glu Glu Val Glu Asn Ser Val Lys His Ile Pro Ser

465 470 475 480

Leu Ala Thr Val Ile Leu Val Lys Thr Met Ile Arg Lys Arg Ser Phe

485 490 495

Gly Asn Pro Phe Glu Gly Ser Arg Arg Glu Glu Arg Ser Leu Ser Ala

500 505 510

Pro Gly Asn Leu Leu Thr Lys Lys Pro Thr Arg Glu Cys Glu Ser Leu

515 520 525

Ser Glu Leu Lys Glu Ala Arg Gln Arg Arg Gln Pro Pro Gly His Arg

530 535 540

Pro Ala Pro Arg Gly Gly Gly Gly Ser Ala Leu Val Arg Gly Ser Pro

545 550 555 560

Cys Val Glu Ser Cys Trp Ala Pro Ala Pro Gly Ser Pro Ala Arg Met

565 570 575

His Pro Leu Arg Pro Glu Glu Ala Met Glu Pro Glu

580 585

<210> SEQ ID NO: 3

<211> LENGTH: 5577

<212> TYPE: DNA

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic

<400> SEQENCE: 3

gagcctgggg aggtcgaggg tgcagcgagc cgtgatcgtg ctactgcact ccagcctggg 60

caacacagag agaccctgtc tcaaaacaaa caaacaaaca aacaaacaaa caaacaaaaa 120

aaacaaagaa aaaaaaatgg gagtgggccg ggcgcggtga ctcacacctg taatcccagc 180

actttcggag gccaaggcgg gtggatcacg aggtcaggaa ttcaagatta gcctggacaa 240

catggtgaaa ccccatctct acgaaaaata caaaaattag ccaagtatgg tggccggcgc 300

ctgtaatccc agctactcgg gagactgagg cagagaactg cttgaacctg ggaggcagag 360

gttgcagtga tccgagatcg cgtcactgca ctccagcgtg ggcgacagag cgagactccg 420

tttcagaaaa gaaaaaaaaa aaaaaaaaaa agggagtcgg ggtggagctc tcattggctc 480

gttgcatgtg agtgtcccta cggcctagaa atacaagaga agcacatcgg aacgggctgg 540

aaatccaccc agttaactag agggctttga accttttatt aacttggagg ttgactctcc 600

tgtcaactcg attccctttt ggctgtttgg cagggtcagt gagacatccc ctgggtcgct 660

cgaccccgta ggacggttca gggagccctc caggtcttcg tttctcctct tccccgcaca 720

gtgctgttat ccagctgggg gatccaacgc acacttaagg ctccagcaaa gtggctccgc 780

tgccggatgg gagtgcccca gtgtgctgga tgaagctggc gcatgcacca tgtcatcatg 840

tgtctctagc cagcccagca gcaaccgggc cgccccccag gatgagctgg ggggcagggg 900

cagcagcagc agcgaaagcc agaagccctg tgaggccctg cggggcctct catccttgag 960

catccacctg ggcatggagt ccttcattgt ggtcaccgag tgtgagccgg gctgtgctgt 1020

ggacctcggc ttggcgcggg accggcccct ggaggccgat ggccaagagg tcccccttga 1080

cacctccggg tcccaggccc ggccccacct ctccggtcgc aagctgtctc tgcaagagcg 1140

gtcccagggt gggctggcag ccggtggcag cctggacatg aacggacgct gcatctgccc 1200

gtccctgccc tactcacccg tcagctcccc gcagtcctcg cctcggctgc cccggcggcc 1260

gacagtggag tctcaccacg tctccatcac gggtatgcag gactgtgtgc agctgaatca 1320

gtataccctg aaggatgaaa ttggaaaggg ctcctatggt gtcgtcaagt tggcctacaa 1380

tgaaaatgac aatacctact atgcaatgaa ggtgctgtcc aaaaagaagc tgatccggca 1440

ggccggcttt ccacgtcgcc ctccaccccg aggcacccgg ccagctcctg gaggctgcat 1500

ccagcccagg ggccccattg agcaggtgta ccaggaaatt gccatcctca agaagctgga 1560

ccaccccaat gtggtgaagc tggtggaggt cctggatgac cccaatgagg accatctgta 1620

catggtgttc gaactggtca accaagggcc cgtgatggaa gtgcccaccc tcaaaccact 1680

ctctgaagac caggcccgtt tctacttcca ggatctgatc aaaggcatcg agtacttaca 1740

ctaccagaag atcatccacc gtgacatcaa accttccaac ctcctggtcg gagaagatgg 1800

gcacatcaag atcgctgact ttggtgtgag caatgaattc aagggcagtg acgcgctcct 1860

ctccaacacc gtgggcacgc ccgccttcat ggcacccgag tcgctctctg agacccgcaa 1920

gatcttctct gggaaggcct tggatgtttg ggccatgggt gtgacactat actgctttgt 1980

ctttggccag tgcccattca tggacgagcg gatcatgtgt ttacacagta agatcaagag 2040

tcaggccctg gaatttccag accagcccga catagctgag gacttgaagg acctgatcac 2100

ccgtatgctg gacaagaacc ccgagtcgag gatcgtggtg ccggaaatca agctgcaccc 2160

ctgggtcacg aggcatgggg cggagccgtt gccgtcggag gatgagaact gcacgctggt 2220

cgaagtgact gaagaggagg tcgagaactc agtcaaacac attcccagct tggcaaccgt 2280

gatcctggtg aagaccatga tacgtaaacg ctcctttggg aacccattcg agggcagccg 2340

gcgggaggaa cgctcactgt cagcgcctgg aaacttgctc acgaagcaag gcagcgaaga 2400

caacctccag ggcaccgacc cgccccccgt gggggaggag gaagtgctct tgtgagaggc 2460

agtccctgcg tggaaagttg ctgggccccc gcccccggct cccccgcacg catgcatcca 2520

ctgcggccgg aggaggccat ggagcccgag tagctgcctg gatcgctcga cctcgcatgc 2580

gcgccgcgtc gcctctgggg ggctgctgca ccgcgtttcc atagcagcat gtcctacgga 2640

aacccagcac gtgtgtagag cctcgatcgt catctctggt tatttgtttt ttcctttgtt 2700

gttttaaagg ggacaaaaaa aaaaaaagga cttgactcca tgacgtcgac cgtggccgct 2760

ggctggctgg acaggcgggt gtgaggagtt gcagacccaa acccacgtgc attttgggac 2820

aattgctttt taaaacgttt ttatgccaaa aatccttcat tgtgattttc agaaccacgt 2880

cagatatacc aagtgactgt gtgtggggtt tgacaactgt ggaaaggcga gcagaaaact 2940

ccggcggtct gaggccatgg aggtggttgc tgcatttgag agggagtagg gggctagatg 3000

tggctcctag tgcaaaccgg aaaccatggc accttccaga gccgtggtct caaggagtca 3060

gagcagggct ggccctcagt agctgcaggg agctttgatg caacttattt gtaagaagga 3120

tttttaaatt ttttatgggt agaattgtag tcaggaaaac agaaagggct tgaaatttaa 3180

taagtgctgc tggaagggga ttttccaagc ctggaagggt attcagcagc tgtggtgggg 3240

aaacatttct cctgaaagac tgaacgtgtt tcttcatgac agctgctcaa agcaggtttc 3300

tgagatagct gaccgagctc tggtaaatct ctttgtcaaa ttacgaaaac ttcagggtga 3360

aatcctatgc ttccatgtac attacatggc ttaagattaa acaaaaacat ttttcaagtc 3420

tctaactaga gtgaactcta gagcacagta gttcagaaac tatttagagc ttccaggata 3480

tatttcacag cttcaggcat gtgatcagtt agagccgatg aaacctatgc ccgcctgtat 3540

atatattagc agcttagcta gttcataacc tgtatattct aaagactgct aaggttttgt 3600

tttcatttta aatcctagct gattgttgtg gtcaatgaaa tacccagttt ctggagggcc 3660

aggtgggaaa tgctttcact ggaccaacac acaaatgatc atcctgagga tctgagcttc 3720

cctagactcc acacaataac cttggggcac ccttttagag aagactgttg aaacccacag 3780

cactcgttgg ggtatgagga aaccagggct tggcacagga agttcccctt tgtagctaaa 3840

agtccagaaa gaaagggttc atctttttga cttccaactg atattgggaa gtttggttga 3900

ggttcaagtg tgactccttc cagagccaca ggtaggggag tgtgaagttg agggggagga 3960

aagctggaag gactctgcct tgggagattc ccagctctgc tttccagcgc ttggtggaat 4020

ctgggctggg gaaagacggc accgggaaac tctgcttccc cattgtttcc atctgatcag 4080

ctgtggtgtg aggacttctc agacaaaggc aaggcctcgt gcccctgccc agcccattca 4140

tggagccctg ggccttcttg gcttccatag atcctaagct cttgactgta gtttagccag 4200

acttgttttg ctatcttata agcagttcag aattagggaa tgctggtttt gaagagcaaa 4260

ggacaggtag tctagagagg gtcgtctggc ctgcttgctg ggtctttgta acccagcact 4320

tcctcttgcc ctcctggctt tatgtttatg gggagaggac tcaatagctc caccccttct 4380

ggcaccagat ggggcttggt tagtttgcaa taagcacctt gcagaggtta aagccagcgg 4440

gtccctagtc ttaggcccag cctgcttgtg tgggctctgg cctggcctgg tggctggccc 4500

agggggcagc agtgcttaga gcttctgcag ggcttctctt gtttacacag ctgcatcaga 4560

caatgccatt tctccccacc acggaacctt ccatctaaga tttcttccag ggaatgccag 4620

caatcaggca gcacccagct gtgggggcag tggggtgggg gagacccaca ttgatgactt 4680

tttttttttc ttttaatgaa gaaacaccaa agaaagctgt ggaaaggacc tgccccacat 4740

gaaaaggata agccaagatg gctgtaaaca cagagcattt gagctgccac tcttggagca 4800

cattgatttt tcaaaagcca gctctgtcag gaaaggaggt gctgttatga gcagctcttc 4860

cagtgggcaa agaggacgcc cataatttct tccattgcta gctcatctgt gggaccaatt 4920

tggtgtaagc aacctgtggc ctgcacttgt ggcctcgaag gaagcacaaa ccctccatcc 4980

acttcccatt tcctctgccc ttttccacct cccccttcca tcccaccagc tgccagtggc 5040

tcccagaaag ccttattgag ccccttgttg acacttgggg ctgcggaggc ctctccctac 5100

tggtctggcc tttcctgaga ggcaggtctt ccgtcctcag agcctttctg gaacaaggag 5160

aatgcctgtg caggtggaca cacaggcctg gcctgtcgct ctcacttgtc ttccagcggg 5220

gagcttcacg ttgccgagtg gaagaaccat gacctccact tgcttccaag gtgctaggga 5280

agtttcaggg tacgctggtt cccctctcca gctggaggcc gagtttctgg ggactgcaga 5340

tttttctact ctgtgatcga ttcaatgccc gatgcttctg tttcattccc gaccctttct 5400

actatgcatt ttccttttat caggtgtata aagttaaata ctgtgtattt atcactaaaa 5460

agtacatgaa cttaagagac aactaagcct ttcgtgtttt tccacaggtg tttaagcttc 5520

tctgtacagt tgaaataaac agacagcaaa atggtgccaa aaaaaaaaaa aaaaaaa 5577

<210> SEQ ID NO: 4

<211> LENGTH: 541

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic

<400> SEQENCE: 4

Met Ser Ser Cys Val Ser Ser Gln Pro Ser Ser Asn Arg Ala Ala Pro

1 5 10 15

Gln Asp Glu Leu Gly Gly Arg Gly Ser Ser Ser Ser Glu Ser Gln Lys

20 25 30

Pro Cys Glu Ala Leu Arg Gly Leu Ser Ser Leu Ser Ile His Leu Gly

35 40 45

Met Glu Ser Phe Ile Val Val Thr Glu Cys Glu Pro Gly Cys Ala Val

50 55 60

Asp Leu Gly Leu Ala Arg Asp Arg Pro Leu Glu Ala Asp Gly Gln Glu

65 70 75 80

Val Pro Leu Asp Thr Ser Gly Ser Gln Ala Arg Pro His Leu Ser Gly

85 90 95

Arg Lys Leu Ser Leu Gln Glu Arg Ser Gln Gly Gly Leu Ala Ala Gly

100 105 110

Gly Ser Leu Asp Met Asn Gly Arg Cys Ile Cys Pro Ser Leu Pro Tyr

115 120 125

Ser Pro Val Ser Ser Pro Gln Ser Ser Pro Arg Leu Pro Arg Arg Pro

130 135 140

Thr Val Glu Ser His His Val Ser Ile Thr Gly Met Gln Asp Cys Val

145 150 155 160

Gln Leu Asn Gln Tyr Thr Leu Lys Asp Glu Ile Gly Lys Gly Ser Tyr

165 170 175

Gly Val Val Lys Leu Ala Tyr Asn Glu Asn Asp Asn Thr Tyr Tyr Ala

180 185 190

Met Lys Val Leu Ser Lys Lys Lys Leu Ile Arg Gln Ala Gly Phe Pro

195 200 205

Arg Arg Pro Pro Pro Arg Gly Thr Arg Pro Ala Pro Gly Gly Cys Ile

210 215 220

Gln Pro Arg Gly Pro Ile Glu Gln Val Tyr Gln Glu Ile Ala Ile Leu

225 230 235 240

Lys Lys Leu Asp His Pro Asn Val Val Lys Leu Val Glu Val Leu Asp

245 250 255

Asp Pro Asn Glu Asp His Leu Tyr Met Val Phe Glu Leu Val Asn Gln

260 265 270

Gly Pro Val Met Glu Val Pro Thr Leu Lys Pro Leu Ser Glu Asp Gln

275 280 285

Ala Arg Phe Tyr Phe Gln Asp Leu Ile Lys Gly Ile Glu Tyr Leu His

290 295 300

Tyr Gln Lys Ile Ile His Arg Asp Ile Lys Pro Ser Asn Leu Leu Val

305 310 315 320

Gly Glu Asp Gly His Ile Lys Ile Ala Asp Phe Gly Val Ser Asn Glu

325 330 335

Phe Lys Gly Ser Asp Ala Leu Leu Ser Asn Thr Val Gly Thr Pro Ala

340 345 350

Phe Met Ala Pro Glu Ser Leu Ser Glu Thr Arg Lys Ile Phe Ser Gly

355 360 365

Lys Ala Leu Asp Val Trp Ala Met Gly Val Thr Leu Tyr Cys Phe Val

370 375 380

Phe Gly Gln Cys Pro Phe Met Asp Glu Arg Ile Met Cys Leu His Ser

385 390 395 400

Lys Ile Lys Ser Gln Ala Leu Glu Phe Pro Asp Gln Pro Asp Ile Ala

405 410 415

Glu Asp Leu Lys Asp Leu Ile Thr Arg Met Leu Asp Lys Asn Pro Glu

420 425 430

Ser Arg Ile Val Val Pro Glu Ile Lys Leu His Pro Trp Val Thr Arg

435 440 445

His Gly Ala Glu Pro Leu Pro Ser Glu Asp Glu Asn Cys Thr Leu Val

450 455 460

Glu Val Thr Glu Glu Glu Val Glu Asn Ser Val Lys His Ile Pro Ser

465 470 475 480

Leu Ala Thr Val Ile Leu Val Lys Thr Met Ile Arg Lys Arg Ser Phe

485 490 495

Gly Asn Pro Phe Glu Gly Ser Arg Arg Glu Glu Arg Ser Leu Ser Ala

500 505 510

Pro Gly Asn Leu Leu Thr Lys Gln Gly Ser Glu Asp Asn Leu Gln Gly

515 520 525

Thr Asp Pro Pro Pro Val Gly Glu Glu Glu Val Leu Leu

530 535 540

<210> SEQ ID NO: 5

<211> LENGTH: 5491

<212> TYPE: DNA

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic

<400> SEQENCE: 5

gagcctgggg aggtcgaggg tgcagcgagc cgtgatcgtg ctactgcact ccagcctggg 60

caacacagag agaccctgtc tcaaaacaaa caaacaaaca aacaaacaaa caaacaaaaa 120

aaacaaagaa aaaaaaatgg gagtgggccg ggcgcggtga ctcacacctg taatcccagc 180

actttcggag gccaaggcgg gtggatcacg aggtcaggaa ttcaagatta gcctggacaa 240

catggtgaaa ccccatctct acgaaaaata caaaaattag ccaagtatgg tggccggcgc 300

ctgtaatccc agctactcgg gagactgagg cagagaactg cttgaacctg ggaggcagag 360

gttgcagtga tccgagatcg cgtcactgca ctccagcgtg ggcgacagag cgagactccg 420

tttcagaaaa gaaaaaaaaa aaaaaaaaaa agggagtcgg ggtggagctc tcattggctc 480

gttgcatgtg agtgtcccta cggcctagaa atacaagaga agcacatcgg aacgggctgg 540

aaatccaccc agttaactag agggctttga accttttatt aacttggagg ttgactctcc 600

tgtcaactcg attccctttt ggctgtttgg cagggtcagt gagacatccc ctgggtcgct 660

cgaccccgta ggacggttca gggagccctc caggtcttcg tttctcctct tccccgcaca 720

gtgctgttat ccagctgggg gatccaacgc acacttaagg ctccagcaaa gtggctccgc 780

tgccggatgg gagtgcccca gtgtgctgga tgaagctggc gcatgcacca tgtcatcatg 840

tgtctctagc cagcccagca gcaaccgggc cgccccccag gatgagctgg ggggcagggg 900

cagcagcagc agcgaaagcc agaagccctg tgaggccctg cggggcctct catccttgag 960

catccacctg ggcatggagt ccttcattgt ggtcaccgag tgtgagccgg gctgtgctgt 1020

ggacctcggc ttggcgcggg accggcccct ggaggccgat ggccaagagg tcccccttga 1080

cacctccggg tcccaggccc ggccccacct ctccggtcgc aagctgtctc tgcaagagcg 1140

gtcccagggt gggctggcag ccggtggcag cctggacatg aacggacgct gcatctgccc 1200

gtccctgccc tactcacccg tcagctcccc gcagtcctcg cctcggctgc cccggcggcc 1260

gacagtggag tctcaccacg tctccatcac gggtatgcag gactgtgtgc agctgaatca 1320

gtataccctg aaggatgaaa ttggaaaggg ctcctatggt gtcgtcaagt tggcctacaa 1380

tgaaaatgac aatacctact atgcaatgaa ggtgctgtcc aaaaagaagc tgatccggca 1440

ggccggcttt ccacgtcgcc ctccaccccg aggcacccgg ccagctcctg gaggctgcat 1500

ccagcccagg ggccccattg agcaggtgta ccaggaaatt gccatcctca agaagctgga 1560

ccaccccaat gtggtgaagc tggtggaggt cctggatgac cccaatgagg accatctgta 1620

catggtgttc gaactggtca accaagggcc cgtgatggaa gtgcccaccc tcaaaccact 1680

ctctgaagac caggcccgtt tctacttcca ggatctgatc aaaggcatcg agtacttaca 1740

ctaccagaag atcatccacc gtgacatcaa accttccaac ctcctggtcg gagaagatgg 1800

gcacatcaag atcgctgact ttggtgtgag caatgaattc aagggcagtg acgcgctcct 1860

ctccaacacc gtgggcacgc ccgccttcat ggcacccgag tcgctctctg agacccgcaa 1920

gatcttctct gggaaggcct tggatgtttg ggccatgggt gtgacactat actgctttgt 1980

ctttggccag tgcccattca tggacgagcg gatcatgtgt ttacacagta agatcaagag 2040

tcaggccctg gaatttccag accagcccga catagctgag gacttgaagg acctgatcac 2100

ccgtatgctg gacaagaacc ccgagtcgag gatcgtggtg ccggaaatca agatcctggt 2160

gaagaccatg atacgtaaac gctcctttgg gaacccattc gagggcagcc ggcgggagga 2220

acgctcactg tcagcgcctg gaaacttgct caccaaaaaa ccaaccaggg aatgtgagtc 2280

cctgtctgag ctcaaggaag caaggcagcg aagacaacct ccagggcacc gacccgcccc 2340

ccgtggggga ggaggaagtg ctcttgtgag aggcagtccc tgcgtggaaa gttgctgggc 2400

ccccgccccc ggctcccccg cacgcatgca tccactgcgg ccggaggagg ccatggagcc 2460

cgagtagctg cctggatcgc tcgacctcgc atgcgcgccg cgtcgcctct ggggggctgc 2520

tgcaccgcgt ttccatagca gcatgtccta cggaaaccca gcacgtgtgt agagcctcga 2580

tcgtcatctc tggttatttg ttttttcctt tgttgtttta aaggggacaa aaaaaaaaaa 2640

aggacttgac tccatgacgt cgaccgtggc cgctggctgg ctggacaggc gggtgtgagg 2700

agttgcagac ccaaacccac gtgcattttg ggacaattgc tttttaaaac gtttttatgc 2760

caaaaatcct tcattgtgat tttcagaacc acgtcagata taccaagtga ctgtgtgtgg 2820

ggtttgacaa ctgtggaaag gcgagcagaa aactccggcg gtctgaggcc atggaggtgg 2880

ttgctgcatt tgagagggag tagggggcta gatgtggctc ctagtgcaaa ccggaaacca 2940

tggcaccttc cagagccgtg gtctcaagga gtcagagcag ggctggccct cagtagctgc 3000

agggagcttt gatgcaactt atttgtaaga aggattttta aattttttat gggtagaatt 3060

gtagtcagga aaacagaaag ggcttgaaat ttaataagtg ctgctggaag gggattttcc 3120

aagcctggaa gggtattcag cagctgtggt ggggaaacat ttctcctgaa agactgaacg 3180

tgtttcttca tgacagctgc tcaaagcagg tttctgagat agctgaccga gctctggtaa 3240

atctctttgt caaattacga aaacttcagg gtgaaatcct atgcttccat gtacattaca 3300

tggcttaaga ttaaacaaaa acatttttca agtctctaac tagagtgaac tctagagcac 3360

agtagttcag aaactattta gagcttccag gatatatttc acagcttcag gcatgtgatc 3420

agttagagcc gatgaaacct atgcccgcct gtatatatat tagcagctta gctagttcat 3480

aacctgtata ttctaaagac tgctaaggtt ttgttttcat tttaaatcct agctgattgt 3540

tgtggtcaat gaaataccca gtttctggag ggccaggtgg gaaatgcttt cactggacca 3600

acacacaaat gatcatcctg aggatctgag cttccctaga ctccacacaa taaccttggg 3660

gcaccctttt agagaagact gttgaaaccc acagcactcg ttggggtatg aggaaaccag 3720

ggcttggcac aggaagttcc cctttgtagc taaaagtcca gaaagaaagg gttcatcttt 3780

ttgacttcca actgatattg ggaagtttgg ttgaggttca agtgtgactc cttccagagc 3840

cacaggtagg ggagtgtgaa gttgaggggg aggaaagctg gaaggactct gccttgggag 3900

attcccagct ctgctttcca gcgcttggtg gaatctgggc tggggaaaga cggcaccggg 3960

aaactctgct tccccattgt ttccatctga tcagctgtgg tgtgaggact tctcagacaa 4020

aggcaaggcc tcgtgcccct gcccagccca ttcatggagc cctgggcctt cttggcttcc 4080

atagatccta agctcttgac tgtagtttag ccagacttgt tttgctatct tataagcagt 4140

tcagaattag ggaatgctgg ttttgaagag caaaggacag gtagtctaga gagggtcgtc 4200

tggcctgctt gctgggtctt tgtaacccag cacttcctct tgccctcctg gctttatgtt 4260

tatggggaga ggactcaata gctccacccc ttctggcacc agatggggct tggttagttt 4320

gcaataagca ccttgcagag gttaaagcca gcgggtccct agtcttaggc ccagcctgct 4380

tgtgtgggct ctggcctggc ctggtggctg gcccaggggg cagcagtgct tagagcttct 4440

gcagggcttc tcttgtttac acagctgcat cagacaatgc catttctccc caccacggaa 4500

ccttccatct aagatttctt ccagggaatg ccagcaatca ggcagcaccc agctgtgggg 4560

gcagtggggt gggggagacc cacattgatg actttttttt tttcttttaa tgaagaaaca 4620

ccaaagaaag ctgtggaaag gacctgcccc acatgaaaag gataagccaa gatggctgta 4680

aacacagagc atttgagctg ccactcttgg agcacattga tttttcaaaa gccagctctg 4740

tcaggaaagg aggtgctgtt atgagcagct cttccagtgg gcaaagagga cgcccataat 4800

ttcttccatt gctagctcat ctgtgggacc aatttggtgt aagcaacctg tggcctgcac 4860

ttgtggcctc gaaggaagca caaaccctcc atccacttcc catttcctct gcccttttcc 4920

acctccccct tccatcccac cagctgccag tggctcccag aaagccttat tgagcccctt 4980

gttgacactt ggggctgcgg aggcctctcc ctactggtct ggcctttcct gagaggcagg 5040

tcttccgtcc tcagagcctt tctggaacaa ggagaatgcc tgtgcaggtg gacacacagg 5100

cctggcctgt cgctctcact tgtcttccag cggggagctt cacgttgccg agtggaagaa 5160

ccatgacctc cacttgcttc caaggtgcta gggaagtttc agggtacgct ggttcccctc 5220

tccagctgga ggccgagttt ctggggactg cagatttttc tactctgtga tcgattcaat 5280

gcccgatgct tctgtttcat tcccgaccct ttctactatg cattttcctt ttatcaggtg 5340

tataaagtta aatactgtgt atttatcact aaaaagtaca tgaacttaag agacaactaa 5400

gcctttcgtg tttttccaca ggtgtttaag cttctctgta cagttgaaat aaacagacag 5460

caaaatggtg ccaaaaaaaa aaaaaaaaaa a 5491

<210> SEQ ID NO: 6

<211> LENGTH: 545

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic

<400> SEQENCE: 6

Met Ser Ser Cys Val Ser Ser Gln Pro Ser Ser Asn Arg Ala Ala Pro

1 5 10 15

Gln Asp Glu Leu Gly Gly Arg Gly Ser Ser Ser Ser Glu Ser Gln Lys

20 25 30

Pro Cys Glu Ala Leu Arg Gly Leu Ser Ser Leu Ser Ile His Leu Gly

35 40 45

Met Glu Ser Phe Ile Val Val Thr Glu Cys Glu Pro Gly Cys Ala Val

50 55 60

Asp Leu Gly Leu Ala Arg Asp Arg Pro Leu Glu Ala Asp Gly Gln Glu

65 70 75 80

Val Pro Leu Asp Thr Ser Gly Ser Gln Ala Arg Pro His Leu Ser Gly

85 90 95

Arg Lys Leu Ser Leu Gln Glu Arg Ser Gln Gly Gly Leu Ala Ala Gly

100 105 110

Gly Ser Leu Asp Met Asn Gly Arg Cys Ile Cys Pro Ser Leu Pro Tyr

115 120 125

Ser Pro Val Ser Ser Pro Gln Ser Ser Pro Arg Leu Pro Arg Arg Pro

130 135 140

Thr Val Glu Ser His His Val Ser Ile Thr Gly Met Gln Asp Cys Val

145 150 155 160

Gln Leu Asn Gln Tyr Thr Leu Lys Asp Glu Ile Gly Lys Gly Ser Tyr

165 170 175

Gly Val Val Lys Leu Ala Tyr Asn Glu Asn Asp Asn Thr Tyr Tyr Ala

180 185 190

Met Lys Val Leu Ser Lys Lys Lys Leu Ile Arg Gln Ala Gly Phe Pro

195 200 205

Arg Arg Pro Pro Pro Arg Gly Thr Arg Pro Ala Pro Gly Gly Cys Ile

210 215 220

Gln Pro Arg Gly Pro Ile Glu Gln Val Tyr Gln Glu Ile Ala Ile Leu

225 230 235 240

Lys Lys Leu Asp His Pro Asn Val Val Lys Leu Val Glu Val Leu Asp

245 250 255

Asp Pro Asn Glu Asp His Leu Tyr Met Val Phe Glu Leu Val Asn Gln

260 265 270

Gly Pro Val Met Glu Val Pro Thr Leu Lys Pro Leu Ser Glu Asp Gln

275 280 285

Ala Arg Phe Tyr Phe Gln Asp Leu Ile Lys Gly Ile Glu Tyr Leu His

290 295 300

Tyr Gln Lys Ile Ile His Arg Asp Ile Lys Pro Ser Asn Leu Leu Val

305 310 315 320

Gly Glu Asp Gly His Ile Lys Ile Ala Asp Phe Gly Val Ser Asn Glu

325 330 335

Phe Lys Gly Ser Asp Ala Leu Leu Ser Asn Thr Val Gly Thr Pro Ala

340 345 350

Phe Met Ala Pro Glu Ser Leu Ser Glu Thr Arg Lys Ile Phe Ser Gly

355 360 365

Lys Ala Leu Asp Val Trp Ala Met Gly Val Thr Leu Tyr Cys Phe Val

370 375 380

Phe Gly Gln Cys Pro Phe Met Asp Glu Arg Ile Met Cys Leu His Ser

385 390 395 400

Lys Ile Lys Ser Gln Ala Leu Glu Phe Pro Asp Gln Pro Asp Ile Ala

405 410 415

Glu Asp Leu Lys Asp Leu Ile Thr Arg Met Leu Asp Lys Asn Pro Glu

420 425 430

Ser Arg Ile Val Val Pro Glu Ile Lys Ile Leu Val Lys Thr Met Ile

435 440 445

Arg Lys Arg Ser Phe Gly Asn Pro Phe Glu Gly Ser Arg Arg Glu Glu

450 455 460

Arg Ser Leu Ser Ala Pro Gly Asn Leu Leu Thr Lys Lys Pro Thr Arg

465 470 475 480

Glu Cys Glu Ser Leu Ser Glu Leu Lys Glu Ala Arg Gln Arg Arg Gln

485 490 495

Pro Pro Gly His Arg Pro Ala Pro Arg Gly Gly Gly Gly Ser Ala Leu

500 505 510

Val Arg Gly Ser Pro Cys Val Glu Ser Cys Trp Ala Pro Ala Pro Gly

515 520 525

Ser Pro Ala Arg Met His Pro Leu Arg Pro Glu Glu Ala Met Glu Pro

530 535 540

Glu

545

<210> SEQ ID NO: 7

<211> LENGTH: 5448

<212> TYPE: DNA

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic

<400> SEQENCE: 7

gagcctgggg aggtcgaggg tgcagcgagc cgtgatcgtg ctactgcact ccagcctggg 60

caacacagag agaccctgtc tcaaaacaaa caaacaaaca aacaaacaaa caaacaaaaa 120

aaacaaagaa aaaaaaatgg gagtgggccg ggcgcggtga ctcacacctg taatcccagc 180

actttcggag gccaaggcgg gtggatcacg aggtcaggaa ttcaagatta gcctggacaa 240

catggtgaaa ccccatctct acgaaaaata caaaaattag ccaagtatgg tggccggcgc 300

ctgtaatccc agctactcgg gagactgagg cagagaactg cttgaacctg ggaggcagag 360

gttgcagtga tccgagatcg cgtcactgca ctccagcgtg ggcgacagag cgagactccg 420

tttcagaaaa gaaaaaaaaa aaaaaaaaaa agggagtcgg ggtggagctc tcattggctc 480

gttgcatgtg agtgtcccta cggcctagaa atacaagaga agcacatcgg aacgggctgg 540

aaatccaccc agttaactag agggctttga accttttatt aacttggagg ttgactctcc 600

tgtcaactcg attccctttt ggctgtttgg cagggtcagt gagacatccc ctgggtcgct 660

cgaccccgta ggacggttca gggagccctc caggtcttcg tttctcctct tccccgcaca 720

gtgctgttat ccagctgggg gatccaacgc acacttaagg ctccagcaaa gtggctccgc 780

tgccggatgg gagtgcccca gtgtgctgga tgaagctggc gcatgcacca tgtcatcatg 840

tgtctctagc cagcccagca gcaaccgggc cgccccccag gatgagctgg ggggcagggg 900

cagcagcagc agcgaaagcc agaagccctg tgaggccctg cggggcctct catccttgag 960

catccacctg ggcatggagt ccttcattgt ggtcaccgag tgtgagccgg gctgtgctgt 1020

ggacctcggc ttggcgcggg accggcccct ggaggccgat ggccaagagg tcccccttga 1080

cacctccggg tcccaggccc ggccccacct ctccggtcgc aagctgtctc tgcaagagcg 1140

gtcccagggt gggctggcag ccggtggcag cctggacatg aacggacgct gcatctgccc 1200

gtccctgccc tactcacccg tcagctcccc gcagtcctcg cctcggctgc cccggcggcc 1260

gacagtggag tctcaccacg tctccatcac gggtatgcag gactgtgtgc agctgaatca 1320

gtataccctg aaggatgaaa ttggaaaggg ctcctatggt gtcgtcaagt tggcctacaa 1380

tgaaaatgac aatacctact atgcaatgaa ggtgctgtcc aaaaagaagc tgatccggca 1440

ggccggcttt ccacgtcgcc ctccaccccg aggcacccgg ccagctcctg gaggctgcat 1500

ccagcccagg ggccccattg agcaggtgta ccaggaaatt gccatcctca agaagctgga 1560

ccaccccaat gtggtgaagc tggtggaggt cctggatgac cccaatgagg accatctgta 1620

catggtgttc gaactggtca accaagggcc cgtgatggaa gtgcccaccc tcaaaccact 1680

ctctgaagac caggcccgtt tctacttcca ggatctgatc aaaggcatcg agtacttaca 1740

ctaccagaag atcatccacc gtgacatcaa accttccaac ctcctggtcg gagaagatgg 1800

gcacatcaag atcgctgact ttggtgtgag caatgaattc aagggcagtg acgcgctcct 1860

ctccaacacc gtgggcacgc ccgccttcat ggcacccgag tcgctctctg agacccgcaa 1920

gatcttctct gggaaggcct tggatgtttg ggccatgggt gtgacactat actgctttgt 1980

ctttggccag tgcccattca tggacgagcg gatcatgtgt ttacacagta agatcaagag 2040

tcaggccctg gaatttccag accagcccga catagctgag gacttgaagg acctgatcac 2100

ccgtatgctg gacaagaacc ccgagtcgag gatcgtggtg ccggaaatca agatcctggt 2160

gaagaccatg atacgtaaac gctcctttgg gaacccattc gagggcagcc ggcgggagga 2220

acgctcactg tcagcgcctg gaaacttgct cacgaagcaa ggcagcgaag acaacctcca 2280

gggcaccgac ccgccccccg tgggggagga ggaagtgctc ttgtgagagg cagtccctgc 2340

gtggaaagtt gctgggcccc cgcccccggc tcccccgcac gcatgcatcc actgcggccg 2400

gaggaggcca tggagcccga gtagctgcct ggatcgctcg acctcgcatg cgcgccgcgt 2460

cgcctctggg gggctgctgc accgcgtttc catagcagca tgtcctacgg aaacccagca 2520

cgtgtgtaga gcctcgatcg tcatctctgg ttatttgttt tttcctttgt tgttttaaag 2580

gggacaaaaa aaaaaaaagg acttgactcc atgacgtcga ccgtggccgc tggctggctg 2640

gacaggcggg tgtgaggagt tgcagaccca aacccacgtg cattttggga caattgcttt 2700

ttaaaacgtt tttatgccaa aaatccttca ttgtgatttt cagaaccacg tcagatatac 2760

caagtgactg tgtgtggggt ttgacaactg tggaaaggcg agcagaaaac tccggcggtc 2820

tgaggccatg gaggtggttg ctgcatttga gagggagtag ggggctagat gtggctccta 2880

gtgcaaaccg gaaaccatgg caccttccag agccgtggtc tcaaggagtc agagcagggc 2940

tggccctcag tagctgcagg gagctttgat gcaacttatt tgtaagaagg atttttaaat 3000

tttttatggg tagaattgta gtcaggaaaa cagaaagggc ttgaaattta ataagtgctg 3060

ctggaagggg attttccaag cctggaaggg tattcagcag ctgtggtggg gaaacatttc 3120

tcctgaaaga ctgaacgtgt ttcttcatga cagctgctca aagcaggttt ctgagatagc 3180

tgaccgagct ctggtaaatc tctttgtcaa attacgaaaa cttcagggtg aaatcctatg 3240

cttccatgta cattacatgg cttaagatta aacaaaaaca tttttcaagt ctctaactag 3300

agtgaactct agagcacagt agttcagaaa ctatttagag cttccaggat atatttcaca 3360

gcttcaggca tgtgatcagt tagagccgat gaaacctatg cccgcctgta tatatattag 3420

cagcttagct agttcataac ctgtatattc taaagactgc taaggttttg ttttcatttt 3480

aaatcctagc tgattgttgt ggtcaatgaa atacccagtt tctggagggc caggtgggaa 3540

atgctttcac tggaccaaca cacaaatgat catcctgagg atctgagctt ccctagactc 3600

cacacaataa ccttggggca cccttttaga gaagactgtt gaaacccaca gcactcgttg 3660

gggtatgagg aaaccagggc ttggcacagg aagttcccct ttgtagctaa aagtccagaa 3720

agaaagggtt catctttttg acttccaact gatattggga agtttggttg aggttcaagt 3780

gtgactcctt ccagagccac aggtagggga gtgtgaagtt gagggggagg aaagctggaa 3840

ggactctgcc ttgggagatt cccagctctg ctttccagcg cttggtggaa tctgggctgg 3900

ggaaagacgg caccgggaaa ctctgcttcc ccattgtttc catctgatca gctgtggtgt 3960

gaggacttct cagacaaagg caaggcctcg tgcccctgcc cagcccattc atggagccct 4020

gggccttctt ggcttccata gatcctaagc tcttgactgt agtttagcca gacttgtttt 4080

gctatcttat aagcagttca gaattaggga atgctggttt tgaagagcaa aggacaggta 4140

gtctagagag ggtcgtctgg cctgcttgct gggtctttgt aacccagcac ttcctcttgc 4200

cctcctggct ttatgtttat ggggagagga ctcaatagct ccaccccttc tggcaccaga 4260

tggggcttgg ttagtttgca ataagcacct tgcagaggtt aaagccagcg ggtccctagt 4320

cttaggccca gcctgcttgt gtgggctctg gcctggcctg gtggctggcc cagggggcag 4380

cagtgcttag agcttctgca gggcttctct tgtttacaca gctgcatcag acaatgccat 4440

ttctccccac cacggaacct tccatctaag atttcttcca gggaatgcca gcaatcaggc 4500

agcacccagc tgtgggggca gtggggtggg ggagacccac attgatgact tttttttttt 4560

cttttaatga agaaacacca aagaaagctg tggaaaggac ctgccccaca tgaaaaggat 4620

aagccaagat ggctgtaaac acagagcatt tgagctgcca ctcttggagc acattgattt 4680

ttcaaaagcc agctctgtca ggaaaggagg tgctgttatg agcagctctt ccagtgggca 4740

aagaggacgc ccataatttc ttccattgct agctcatctg tgggaccaat ttggtgtaag 4800

caacctgtgg cctgcacttg tggcctcgaa ggaagcacaa accctccatc cacttcccat 4860

ttcctctgcc cttttccacc tcccccttcc atcccaccag ctgccagtgg ctcccagaaa 4920

gccttattga gccccttgtt gacacttggg gctgcggagg cctctcccta ctggtctggc 4980

ctttcctgag aggcaggtct tccgtcctca gagcctttct ggaacaagga gaatgcctgt 5040

gcaggtggac acacaggcct ggcctgtcgc tctcacttgt cttccagcgg ggagcttcac 5100

gttgccgagt ggaagaacca tgacctccac ttgcttccaa ggtgctaggg aagtttcagg 5160

gtacgctggt tcccctctcc agctggaggc cgagtttctg gggactgcag atttttctac 5220

tctgtgatcg attcaatgcc cgatgcttct gtttcattcc cgaccctttc tactatgcat 5280

tttcctttta tcaggtgtat aaagttaaat actgtgtatt tatcactaaa aagtacatga 5340

acttaagaga caactaagcc tttcgtgttt ttccacaggt gtttaagctt ctctgtacag 5400

ttgaaataaa cagacagcaa aatggtgcca aaaaaaaaaa aaaaaaaa 5448

<210> SEQ ID NO: 8

<211> LENGTH: 498

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic

<400> SEQENCE: 8

Met Ser Ser Cys Val Ser Ser Gln Pro Ser Ser Asn Arg Ala Ala Pro

1 5 10 15

Gln Asp Glu Leu Gly Gly Arg Gly Ser Ser Ser Ser Glu Ser Gln Lys

20 25 30

Pro Cys Glu Ala Leu Arg Gly Leu Ser Ser Leu Ser Ile His Leu Gly

35 40 45

Met Glu Ser Phe Ile Val Val Thr Glu Cys Glu Pro Gly Cys Ala Val

50 55 60

Asp Leu Gly Leu Ala Arg Asp Arg Pro Leu Glu Ala Asp Gly Gln Glu

65 70 75 80

Val Pro Leu Asp Thr Ser Gly Ser Gln Ala Arg Pro His Leu Ser Gly

85 90 95

Arg Lys Leu Ser Leu Gln Glu Arg Ser Gln Gly Gly Leu Ala Ala Gly

100 105 110

Gly Ser Leu Asp Met Asn Gly Arg Cys Ile Cys Pro Ser Leu Pro Tyr

115 120 125

Ser Pro Val Ser Ser Pro Gln Ser Ser Pro Arg Leu Pro Arg Arg Pro

130 135 140

Thr Val Glu Ser His His Val Ser Ile Thr Gly Met Gln Asp Cys Val

145 150 155 160

Gln Leu Asn Gln Tyr Thr Leu Lys Asp Glu Ile Gly Lys Gly Ser Tyr

165 170 175

Gly Val Val Lys Leu Ala Tyr Asn Glu Asn Asp Asn Thr Tyr Tyr Ala

180 185 190

Met Lys Val Leu Ser Lys Lys Lys Leu Ile Arg Gln Ala Gly Phe Pro

195 200 205

Arg Arg Pro Pro Pro Arg Gly Thr Arg Pro Ala Pro Gly Gly Cys Ile

210 215 220

Gln Pro Arg Gly Pro Ile Glu Gln Val Tyr Gln Glu Ile Ala Ile Leu

225 230 235 240

Lys Lys Leu Asp His Pro Asn Val Val Lys Leu Val Glu Val Leu Asp

245 250 255

Asp Pro Asn Glu Asp His Leu Tyr Met Val Phe Glu Leu Val Asn Gln

260 265 270

Gly Pro Val Met Glu Val Pro Thr Leu Lys Pro Leu Ser Glu Asp Gln

275 280 285

Ala Arg Phe Tyr Phe Gln Asp Leu Ile Lys Gly Ile Glu Tyr Leu His

290 295 300

Tyr Gln Lys Ile Ile His Arg Asp Ile Lys Pro Ser Asn Leu Leu Val

305 310 315 320

Gly Glu Asp Gly His Ile Lys Ile Ala Asp Phe Gly Val Ser Asn Glu

325 330 335

Phe Lys Gly Ser Asp Ala Leu Leu Ser Asn Thr Val Gly Thr Pro Ala

340 345 350

Phe Met Ala Pro Glu Ser Leu Ser Glu Thr Arg Lys Ile Phe Ser Gly

355 360 365

Lys Ala Leu Asp Val Trp Ala Met Gly Val Thr Leu Tyr Cys Phe Val

370 375 380

Phe Gly Gln Cys Pro Phe Met Asp Glu Arg Ile Met Cys Leu His Ser

385 390 395 400

Lys Ile Lys Ser Gln Ala Leu Glu Phe Pro Asp Gln Pro Asp Ile Ala

405 410 415

Glu Asp Leu Lys Asp Leu Ile Thr Arg Met Leu Asp Lys Asn Pro Glu

420 425 430

Ser Arg Ile Val Val Pro Glu Ile Lys Ile Leu Val Lys Thr Met Ile

435 440 445

Arg Lys Arg Ser Phe Gly Asn Pro Phe Glu Gly Ser Arg Arg Glu Glu

450 455 460

Arg Ser Leu Ser Ala Pro Gly Asn Leu Leu Thr Lys Gln Gly Ser Glu

465 470 475 480

Asp Asn Leu Gln Gly Thr Asp Pro Pro Pro Val Gly Glu Glu Glu Val

485 490 495

Leu Leu

<210> SEQ ID NO: 9

<211> LENGTH: 2981

<212> TYPE: DNA

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic

<400> SEQENCE: 9

gagcctgggg aggtcgaggg tgcagcgagc cgtgatcgtg ctactgcact ccagcctggg 60

caacacagag agaccctgtc tcaaaacaaa caaacaaaca aacaaacaaa caaacaaaaa 120

aaacaaagaa aaaaaaatgg gagtgggccg ggcgcggtga ctcacacctg taatcccagc 180

actttcggag gccaaggcgg gtggatcacg aggtcaggaa ttcaagatta gcctggacaa 240

catggtgaaa ccccatctct acgaaaaata caaaaattag ccaagtatgg tggccggcgc 300

ctgtaatccc agctactcgg gagactgagg cagagaactg cttgaacctg ggaggcagag 360

gttgcagtga tccgagatcg cgtcactgca ctccagcgtg ggcgacagag cgagactccg 420

tttcagaaaa gaaaaaaaaa aaaaaaaaaa agggagtcgg ggtggagctc tcattggctc 480

gttgcatgtg agtgtcccta cggcctagaa atacaagaga agcacatcgg aacgggctgg 540

aaatccaccc agttaactag agggctttga accttttatt aacttggagg ttgactctcc 600

tgtcaactcg attccctttt ggctgtttgg cagggtcagt gagacatccc ctgggtcgct 660

cgaccccgta ggacggttca gggagccctc caggtcttcg tttctcctct tccccgcaca 720

gtgctgttat ccagctgggg gatccaacgc acacttaagg ctccagcaaa gtggctccgc 780

tgccggatgg gagtgcccca gtgtgctgga tgaagctggc gcatgcacca tgtcatcatg 840

tgtctctagc cagcccagca gcaaccgggc cgccccccag gatgagctgg ggggcagggg 900

cagcagcagc agcgaaagcc agaagccctg tgaggccctg cggggcctct catccttgag 960

catccacctg ggcatggagt ccttcattgt ggtcaccgag tgtgagccgg gctgtgctgt 1020

ggacctcggc ttggcgcggg accggcccct ggaggccgat ggccaagagg tcccccttga 1080

cacctccggg tcccaggccc ggccccacct ctccggtcgc aagctgtctc tgcaagagcg 1140

gtcccagggt gggctggcag ccggtggcag cctggacatg aacggacgct gcatctgccc 1200

gtccctgccc tactcacccg tcagctcccc gcagtcctcg cctcggctgc cccggcggcc 1260

gacagtggag tctcaccacg tctccatcac gggtatgcag gactgtgtgc agctgaatca 1320

gtataccctg aaggatgaaa ttggaaaggg ctcctatggt gtcgtcaagt tggcctacaa 1380

tgaaaatgac aatacctact atgcaatgaa ggtgctgtcc aaaaagaagc tgatccggca 1440

ggccggcttt ccacgtcgcc ctccaccccg aggcacccgg ccagctcctg gaggctgcat 1500

ccagcccagg ggccccattg agcaggtgta ccaggaaatt gccatcctca agaagctgga 1560

ccaccccaat gtggtgaagc tggtggaggt cctggatgac cccaatgagg accatctgta 1620

catggtgttc gaactggtca accaagggcc cgtgatggaa gtgcccaccc tcaaaccact 1680

ctctgaagac caggcccgtt tctacttcca ggatctgatc aaaggcatcg agtacttaca 1740

ctaccagaag atcatccacc gtgacatcaa accttccaac ctcctggtcg gagaagatgg 1800

gcacatcaag atcgctgact ttggtgtgag caatgaattc aagggcagtg acgcgctcct 1860

ctccaacacc gtgggcacgc ccgccttcat ggcacccgag tcgctctctg agacccgcaa 1920

gatcttctct gggaaggcct tggatgtttg ggccatgggt gtgacactat actgctttgt 1980

ctttggccag tgcccattca tggacgagcg gatcatgtgt ttacacagta agatcaagag 2040

tcaggccctg gaatttccag accagcccga catagctgag gacttgaagg acctgatcac 2100

ccgtatgctg gacaagaacc ccgagtcgag gatcgtggtg ccggaaatca agctgcaccc 2160

ctgggtcacg aggcatgggg cggagccgtt gccgtcggag gatgagaact gcacgctggt 2220

cgaagtgact gaagaggagg tcgagaactc agtcaaacac attcccagct tggcaaccgt 2280

gatcctggtg aagaccatga tacgtaaacg ctcctttggg aacccattcg agggcagccg 2340

gcgggaggaa cgctcactgt cagcgcctgg aaacttgctc accaaaaaac caaccaggga 2400

atgtgagtcc ctgtctgagc tcaagaccta gaaaataagt ccccttcctg cctgttgcaa 2460

agtaacgtaa gagttccctc acccgagtgg atgcagacct tcttgctgtc agccaccctt 2520

ccttcataca catagccagc ccaggtgacc agaacctccc aggacagatg aggctttgtg 2580

tccttatgag actgggagaa cctgctgggc acccctgctg caggtgctgt ggtgggtggg 2640

gaccccactg cccttcccac tgagcacatc atggctacct gacttggtgg gagctccagg 2700

cagtcacttc tgtttcttaa acatagcttt actgaggtac aattcacata ccatgtaatt 2760

cacccacggg aagtgtatga ttcagtggtt tctaatacag acttctgcag ccattaccac 2820

cgtcaacttt acgacatttt catcagccca agaagacacc ctacactcct tagctgtccc 2880

catccaactc ccccacccca gtaaccactc agaataggta tggatttgcc tattctggac 2940

gtttcgtata aatggcgtca tacactaaaa aaaaaaaaaa a 2981

<210> SEQ ID NO: 10

<211> LENGTH: 533

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic

<400> SEQENCE: 10

Met Ser Ser Cys Val Ser Ser Gln Pro Ser Ser Asn Arg Ala Ala Pro

1 5 10 15

Gln Asp Glu Leu Gly Gly Arg Gly Ser Ser Ser Ser Glu Ser Gln Lys

20 25 30

Pro Cys Glu Ala Leu Arg Gly Leu Ser Ser Leu Ser Ile His Leu Gly

35 40 45

Met Glu Ser Phe Ile Val Val Thr Glu Cys Glu Pro Gly Cys Ala Val

50 55 60

Asp Leu Gly Leu Ala Arg Asp Arg Pro Leu Glu Ala Asp Gly Gln Glu

65 70 75 80

Val Pro Leu Asp Thr Ser Gly Ser Gln Ala Arg Pro His Leu Ser Gly

85 90 95

Arg Lys Leu Ser Leu Gln Glu Arg Ser Gln Gly Gly Leu Ala Ala Gly

100 105 110

Gly Ser Leu Asp Met Asn Gly Arg Cys Ile Cys Pro Ser Leu Pro Tyr

115 120 125

Ser Pro Val Ser Ser Pro Gln Ser Ser Pro Arg Leu Pro Arg Arg Pro

130 135 140

Thr Val Glu Ser His His Val Ser Ile Thr Gly Met Gln Asp Cys Val

145 150 155 160

Gln Leu Asn Gln Tyr Thr Leu Lys Asp Glu Ile Gly Lys Gly Ser Tyr

165 170 175

Gly Val Val Lys Leu Ala Tyr Asn Glu Asn Asp Asn Thr Tyr Tyr Ala

180 185 190

Met Lys Val Leu Ser Lys Lys Lys Leu Ile Arg Gln Ala Gly Phe Pro

195 200 205

Arg Arg Pro Pro Pro Arg Gly Thr Arg Pro Ala Pro Gly Gly Cys Ile

210 215 220

Gln Pro Arg Gly Pro Ile Glu Gln Val Tyr Gln Glu Ile Ala Ile Leu

225 230 235 240

Lys Lys Leu Asp His Pro Asn Val Val Lys Leu Val Glu Val Leu Asp

245 250 255

Asp Pro Asn Glu Asp His Leu Tyr Met Val Phe Glu Leu Val Asn Gln

260 265 270

Gly Pro Val Met Glu Val Pro Thr Leu Lys Pro Leu Ser Glu Asp Gln

275 280 285

Ala Arg Phe Tyr Phe Gln Asp Leu Ile Lys Gly Ile Glu Tyr Leu His

290 295 300

Tyr Gln Lys Ile Ile His Arg Asp Ile Lys Pro Ser Asn Leu Leu Val

305 310 315 320

Gly Glu Asp Gly His Ile Lys Ile Ala Asp Phe Gly Val Ser Asn Glu

325 330 335

Phe Lys Gly Ser Asp Ala Leu Leu Ser Asn Thr Val Gly Thr Pro Ala

340 345 350

Phe Met Ala Pro Glu Ser Leu Ser Glu Thr Arg Lys Ile Phe Ser Gly

355 360 365

Lys Ala Leu Asp Val Trp Ala Met Gly Val Thr Leu Tyr Cys Phe Val

370 375 380

Phe Gly Gln Cys Pro Phe Met Asp Glu Arg Ile Met Cys Leu His Ser

385 390 395 400

Lys Ile Lys Ser Gln Ala Leu Glu Phe Pro Asp Gln Pro Asp Ile Ala

405 410 415

Glu Asp Leu Lys Asp Leu Ile Thr Arg Met Leu Asp Lys Asn Pro Glu

420 425 430

Ser Arg Ile Val Val Pro Glu Ile Lys Leu His Pro Trp Val Thr Arg

435 440 445

His Gly Ala Glu Pro Leu Pro Ser Glu Asp Glu Asn Cys Thr Leu Val

450 455 460

Glu Val Thr Glu Glu Glu Val Glu Asn Ser Val Lys His Ile Pro Ser

465 470 475 480

Leu Ala Thr Val Ile Leu Val Lys Thr Met Ile Arg Lys Arg Ser Phe

485 490 495

Gly Asn Pro Phe Glu Gly Ser Arg Arg Glu Glu Arg Ser Leu Ser Ala

500 505 510

Pro Gly Asn Leu Leu Thr Lys Lys Pro Thr Arg Glu Cys Glu Ser Leu

515 520 525

Ser Glu Leu Lys Thr

530

<210> SEQ ID NO: 11

<211> LENGTH: 2852

<212> TYPE: DNA

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic

<400> SEQENCE: 11

gagcctgggg aggtcgaggg tgcagcgagc cgtgatcgtg ctactgcact ccagcctggg 60

caacacagag agaccctgtc tcaaaacaaa caaacaaaca aacaaacaaa caaacaaaaa 120

aaacaaagaa aaaaaaatgg gagtgggccg ggcgcggtga ctcacacctg taatcccagc 180

actttcggag gccaaggcgg gtggatcacg aggtcaggaa ttcaagatta gcctggacaa 240

catggtgaaa ccccatctct acgaaaaata caaaaattag ccaagtatgg tggccggcgc 300

ctgtaatccc agctactcgg gagactgagg cagagaactg cttgaacctg ggaggcagag 360

gttgcagtga tccgagatcg cgtcactgca ctccagcgtg ggcgacagag cgagactccg 420

tttcagaaaa gaaaaaaaaa aaaaaaaaaa agggagtcgg ggtggagctc tcattggctc 480

gttgcatgtg agtgtcccta cggcctagaa atacaagaga agcacatcgg aacgggctgg 540

aaatccaccc agttaactag agggctttga accttttatt aacttggagg ttgactctcc 600

tgtcaactcg attccctttt ggctgtttgg cagggtcagt gagacatccc ctgggtcgct 660

cgaccccgta ggacggttca gggagccctc caggtcttcg tttctcctct tccccgcaca 720

gtgctgttat ccagctgggg gatccaacgc acacttaagg ctccagcaaa gtggctccgc 780

tgccggatgg gagtgcccca gtgtgctgga tgaagctggc gcatgcacca tgtcatcatg 840

tgtctctagc cagcccagca gcaaccgggc cgccccccag gatgagctgg ggggcagggg 900

cagcagcagc agcgaaagcc agaagccctg tgaggccctg cggggcctct catccttgag 960

catccacctg ggcatggagt ccttcattgt ggtcaccgag tgtgagccgg gctgtgctgt 1020

ggacctcggc ttggcgcggg accggcccct ggaggccgat ggccaagagg tcccccttga 1080

cacctccggg tcccaggccc ggccccacct ctccggtcgc aagctgtctc tgcaagagcg 1140

gtcccagggt gggctggcag ccggtggcag cctggacatg aacggacgct gcatctgccc 1200

gtccctgccc tactcacccg tcagctcccc gcagtcctcg cctcggctgc cccggcggcc 1260

gacagtggag tctcaccacg tctccatcac gggtatgcag gactgtgtgc agctgaatca 1320

gtataccctg aaggatgaaa ttggaaaggg ctcctatggt gtcgtcaagt tggcctacaa 1380

tgaaaatgac aatacctact atgcaatgaa ggtgctgtcc aaaaagaagc tgatccggca 1440

ggccggcttt ccacgtcgcc ctccaccccg aggcacccgg ccagctcctg gaggctgcat 1500

ccagcccagg ggccccattg agcaggtgta ccaggaaatt gccatcctca agaagctgga 1560

ccaccccaat gtggtgaagc tggtggaggt cctggatgac cccaatgagg accatctgta 1620

catggtgttc gaactggtca accaagggcc cgtgatggaa gtgcccaccc tcaaaccact 1680

ctctgaagac caggcccgtt tctacttcca ggatctgatc aaaggcatcg agtacttaca 1740

ctaccagaag atcatccacc gtgacatcaa accttccaac ctcctggtcg gagaagatgg 1800

gcacatcaag atcgctgact ttggtgtgag caatgaattc aagggcagtg acgcgctcct 1860

ctccaacacc gtgggcacgc ccgccttcat ggcacccgag tcgctctctg agacccgcaa 1920

gatcttctct gggaaggcct tggatgtttg ggccatgggt gtgacactat actgctttgt 1980

ctttggccag tgcccattca tggacgagcg gatcatgtgt ttacacagta agatcaagag 2040

tcaggccctg gaatttccag accagcccga catagctgag gacttgaagg acctgatcac 2100

ccgtatgctg gacaagaacc ccgagtcgag gatcgtggtg ccggaaatca agatcctggt 2160

gaagaccatg atacgtaaac gctcctttgg gaacccattc gagggcagcc ggcgggagga 2220

acgctcactg tcagcgcctg gaaacttgct caccaaaaaa ccaaccaggg aatgtgagtc 2280

cctgtctgag ctcaagacct agaaaataag tccccttcct gcctgttgca aagtaacgta 2340

agagttccct cacccgagtg gatgcagacc ttcttgctgt cagccaccct tccttcatac 2400

acatagccag cccaggtgac cagaacctcc caggacagat gaggctttgt gtccttatga 2460

gactgggaga acctgctggg cacccctgct gcaggtgctg tggtgggtgg ggaccccact 2520

gcccttccca ctgagcacat catggctacc tgacttggtg ggagctccag gcagtcactt 2580

ctgtttctta aacatagctt tactgaggta caattcacat accatgtaat tcacccacgg 2640

gaagtgtatg attcagtggt ttctaataca gacttctgca gccattacca ccgtcaactt 2700

tacgacattt tcatcagccc aagaagacac cctacactcc ttagctgtcc ccatccaact 2760

cccccacccc agtaaccact cagaataggt atggatttgc ctattctgga cgtttcgtat 2820

aaatggcgtc atacactaaa aaaaaaaaaa aa 2852

<210> SEQ ID NO: 12

<211> LENGTH: 490

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic

<400> SEQENCE: 12

Met Ser Ser Cys Val Ser Ser Gln Pro Ser Ser Asn Arg Ala Ala Pro

1 5 10 15

Gln Asp Glu Leu Gly Gly Arg Gly Ser Ser Ser Ser Glu Ser Gln Lys

20 25 30

Pro Cys Glu Ala Leu Arg Gly Leu Ser Ser Leu Ser Ile His Leu Gly

35 40 45

Met Glu Ser Phe Ile Val Val Thr Glu Cys Glu Pro Gly Cys Ala Val

50 55 60

Asp Leu Gly Leu Ala Arg Asp Arg Pro Leu Glu Ala Asp Gly Gln Glu

65 70 75 80

Val Pro Leu Asp Thr Ser Gly Ser Gln Ala Arg Pro His Leu Ser Gly

85 90 95

Arg Lys Leu Ser Leu Gln Glu Arg Ser Gln Gly Gly Leu Ala Ala Gly

100 105 110

Gly Ser Leu Asp Met Asn Gly Arg Cys Ile Cys Pro Ser Leu Pro Tyr

115 120 125

Ser Pro Val Ser Ser Pro Gln Ser Ser Pro Arg Leu Pro Arg Arg Pro

130 135 140

Thr Val Glu Ser His His Val Ser Ile Thr Gly Met Gln Asp Cys Val

145 150 155 160

Gln Leu Asn Gln Tyr Thr Leu Lys Asp Glu Ile Gly Lys Gly Ser Tyr

165 170 175

Gly Val Val Lys Leu Ala Tyr Asn Glu Asn Asp Asn Thr Tyr Tyr Ala

180 185 190

Met Lys Val Leu Ser Lys Lys Lys Leu Ile Arg Gln Ala Gly Phe Pro

195 200 205

Arg Arg Pro Pro Pro Arg Gly Thr Arg Pro Ala Pro Gly Gly Cys Ile

210 215 220

Gln Pro Arg Gly Pro Ile Glu Gln Val Tyr Gln Glu Ile Ala Ile Leu

225 230 235 240

Lys Lys Leu Asp His Pro Asn Val Val Lys Leu Val Glu Val Leu Asp

245 250 255

Asp Pro Asn Glu Asp His Leu Tyr Met Val Phe Glu Leu Val Asn Gln

260 265 270

Gly Pro Val Met Glu Val Pro Thr Leu Lys Pro Leu Ser Glu Asp Gln

275 280 285

Ala Arg Phe Tyr Phe Gln Asp Leu Ile Lys Gly Ile Glu Tyr Leu His

290 295 300

Tyr Gln Lys Ile Ile His Arg Asp Ile Lys Pro Ser Asn Leu Leu Val

305 310 315 320

Gly Glu Asp Gly His Ile Lys Ile Ala Asp Phe Gly Val Ser Asn Glu

325 330 335

Phe Lys Gly Ser Asp Ala Leu Leu Ser Asn Thr Val Gly Thr Pro Ala

340 345 350

Phe Met Ala Pro Glu Ser Leu Ser Glu Thr Arg Lys Ile Phe Ser Gly

355 360 365

Lys Ala Leu Asp Val Trp Ala Met Gly Val Thr Leu Tyr Cys Phe Val

370 375 380

Phe Gly Gln Cys Pro Phe Met Asp Glu Arg Ile Met Cys Leu His Ser

385 390 395 400

Lys Ile Lys Ser Gln Ala Leu Glu Phe Pro Asp Gln Pro Asp Ile Ala

405 410 415

Glu Asp Leu Lys Asp Leu Ile Thr Arg Met Leu Asp Lys Asn Pro Glu

420 425 430

Ser Arg Ile Val Val Pro Glu Ile Lys Ile Leu Val Lys Thr Met Ile

435 440 445

Arg Lys Arg Ser Phe Gly Asn Pro Phe Glu Gly Ser Arg Arg Glu Glu

450 455 460

Arg Ser Leu Ser Ala Pro Gly Asn Leu Leu Thr Lys Lys Pro Thr Arg

465 470 475 480

Glu Cys Glu Ser Leu Ser Glu Leu Lys Thr

485 490

<210> SEQ ID NO: 13

<211> LENGTH: 4923

<212> TYPE: DNA

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic

<400> SEQENCE: 13

gcgcgcccgc cgcccgggcg gaggagagga gcgcgcggcc gcgcagagca agctgagccg 60

agccgagccg agctgggggc gcagagcgcg ggaggcggcg gcggcgcgga gcccaggtgg 120

ctccgctgcc ggatgggagt gccccagtgt gctggatgaa gctggcgcat gcaccatgtc 180

atcatgtgtc tctagccagc ccagcagcaa ccgggccgcc ccccaggatg agctgggggg 240

caggggcagc agcagcagcg aaagccagaa gccctgtgag gccctgcggg gcctctcatc 300

cttgagcatc cacctgggca tggagtcctt cattgtggtc accgagtgtg agccgggctg 360

tgctgtggac ctcggcttgg cgcgggaccg gcccctggag gccgatggcc aagaggtccc 420

ccttgacacc tccgggtccc aggcccggcc ccacctctcc ggtcgcaagc tgtctctgca 480

agagcggtcc cagggtgggc tggcagccgg tggcagcctg gacatgaacg gacgctgcat 540

ctgcccgtcc ctgccctact cacccgtcag ctccccgcag tcctcgcctc ggctgccccg 600

gcggccgaca gtggagtctc accacgtctc catcacgggt atgcaggact gtgtgcagct 660

gaatcagtat accctgaagg atgaaattgg aaagggctcc tatggtgtcg tcaagttggc 720

ctacaatgaa aatgacaata cctactatgc aatgaaggtg ctgtccaaaa agaagctgat 780

ccggcaggcc ggctttccac gtcgccctcc accccgaggc acccggccag ctcctggagg 840

ctgcatccag cccaggggcc ccattgagca ggtgtaccag gaaattgcca tcctcaagaa 900

gctggaccac cccaatgtgg tgaagctggt ggaggtcctg gatgacccca atgaggacca 960

tctgtacatg gtgttcgaac tggtcaacca agggcccgtg atggaagtgc ccaccctcaa 1020

accactctct gaagaccagg cccgtttcta cttccaggat ctgatcaaag gcatcgagta 1080

cttacactac cagaagatca tccaccgtga catcaaacct tccaacctcc tggtcggaga 1140

agatgggcac atcaagatcg ctgactttgg tgtgagcaat gaattcaagg gcagtgacgc 1200

gctcctctcc aacaccgtgg gcacgcccgc cttcatggca cccgagtcgc tctctgagac 1260

ccgcaagatc ttctctggga aggccttgga tgtttgggcc atgggtgtga cactatactg 1320

ctttgtcttt ggccagtgcc cattcatgga cgagcggatc atgtgtttac acagtaagat 1380

caagagtcag gccctggaat ttccagacca gcccgacata gctgaggact tgaaggacct 1440

gatcacccgt atgctggaca agaaccccga gtcgaggatc gtggtgccgg aaatcaagct 1500

gcacccctgg gtcacgaggc atggggcgga gccgttgccg tcggaggatg agaactgcac 1560

gctggtcgaa gtgactgaag aggaggtcga gaactcagtc aaacacattc ccagcttggc 1620

aaccgtgatc ctggtgaaga ccatgatacg taaacgctcc tttgggaacc cattcgaggg 1680

cagccggcgg gaggaacgct cactgtcagc gcctggaaac ttgctcacga agcaaggcag 1740

cgaagacaac ctccagggca ccgacccgcc ccccgtgggg gaggaggaag tgctcttgtg 1800

agaggcagtc cctgcgtgga aagttgctgg gcccccgccc ccggctcccc cgcacgcatg 1860

catccactgc ggccggagga ggccatggag cccgagtagc tgcctggatc gctcgacctc 1920

gcatgcgcgc cgcgtcgcct ctggggggct gctgcaccgc gtttccatag cagcatgtcc 1980

tacggaaacc cagcacgtgt gtagagcctc gatcgtcatc tctggttatt tgttttttcc 2040

tttgttgttt taaaggggac aaaaaaaaaa aaaggacttg actccatgac gtcgaccgtg 2100

gccgctggct ggctggacag gcgggtgtga ggagttgcag acccaaaccc acgtgcattt 2160

tgggacaatt gctttttaaa acgtttttat gccaaaaatc cttcattgtg attttcagaa 2220

ccacgtcaga tataccaagt gactgtgtgt ggggtttgac aactgtggaa aggcgagcag 2280

aaaactccgg cggtctgagg ccatggaggt ggttgctgca tttgagaggg agtagggggc 2340

tagatgtggc tcctagtgca aaccggaaac catggcacct tccagagccg tggtctcaag 2400

gagtcagagc agggctggcc ctcagtagct gcagggagct ttgatgcaac ttatttgtaa 2460

gaaggatttt taaatttttt atgggtagaa ttgtagtcag gaaaacagaa agggcttgaa 2520

atttaataag tgctgctgga aggggatttt ccaagcctgg aagggtattc agcagctgtg 2580

gtggggaaac atttctcctg aaagactgaa cgtgtttctt catgacagct gctcaaagca 2640

ggtttctgag atagctgacc gagctctggt aaatctcttt gtcaaattac gaaaacttca 2700

gggtgaaatc ctatgcttcc atgtacatta catggcttaa gattaaacaa aaacattttt 2760

caagtctcta actagagtga actctagagc acagtagttc agaaactatt tagagcttcc 2820

aggatatatt tcacagcttc aggcatgtga tcagttagag ccgatgaaac ctatgcccgc 2880

ctgtatatat attagcagct tagctagttc ataacctgta tattctaaag actgctaagg 2940

ttttgttttc attttaaatc ctagctgatt gttgtggtca atgaaatacc cagtttctgg 3000

agggccaggt gggaaatgct ttcactggac caacacacaa atgatcatcc tgaggatctg 3060

agcttcccta gactccacac aataaccttg gggcaccctt ttagagaaga ctgttgaaac 3120

ccacagcact cgttggggta tgaggaaacc agggcttggc acaggaagtt cccctttgta 3180

gctaaaagtc cagaaagaaa gggttcatct ttttgacttc caactgatat tgggaagttt 3240

ggttgaggtt caagtgtgac tccttccaga gccacaggta ggggagtgtg aagttgaggg 3300

ggaggaaagc tggaaggact ctgccttggg agattcccag ctctgctttc cagcgcttgg 3360

tggaatctgg gctggggaaa gacggcaccg ggaaactctg cttccccatt gtttccatct 3420

gatcagctgt ggtgtgagga cttctcagac aaaggcaagg cctcgtgccc ctgcccagcc 3480

cattcatgga gccctgggcc ttcttggctt ccatagatcc taagctcttg actgtagttt 3540

agccagactt gttttgctat cttataagca gttcagaatt agggaatgct ggttttgaag 3600

agcaaaggac aggtagtcta gagagggtcg tctggcctgc ttgctgggtc tttgtaaccc 3660

agcacttcct cttgccctcc tggctttatg tttatgggga gaggactcaa tagctccacc 3720

ccttctggca ccagatgggg cttggttagt ttgcaataag caccttgcag aggttaaagc 3780

cagcgggtcc ctagtcttag gcccagcctg cttgtgtggg ctctggcctg gcctggtggc 3840

tggcccaggg ggcagcagtg cttagagctt ctgcagggct tctcttgttt acacagctgc 3900

atcagacaat gccatttctc cccaccacgg aaccttccat ctaagatttc ttccagggaa 3960

tgccagcaat caggcagcac ccagctgtgg gggcagtggg gtgggggaga cccacattga 4020

tgactttttt tttttctttt aatgaagaaa caccaaagaa agctgtggaa aggacctgcc 4080

ccacatgaaa aggataagcc aagatggctg taaacacaga gcatttgagc tgccactctt 4140

ggagcacatt gatttttcaa aagccagctc tgtcaggaaa ggaggtgctg ttatgagcag 4200

ctcttccagt gggcaaagag gacgcccata atttcttcca ttgctagctc atctgtggga 4260

ccaatttggt gtaagcaacc tgtggcctgc acttgtggcc tcgaaggaag cacaaaccct 4320

ccatccactt cccatttcct ctgccctttt ccacctcccc cttccatccc accagctgcc 4380

agtggctccc agaaagcctt attgagcccc ttgttgacac ttggggctgc ggaggcctct 4440

ccctactggt ctggcctttc ctgagaggca ggtcttccgt cctcagagcc tttctggaac 4500

aaggagaatg cctgtgcagg tggacacaca ggcctggcct gtcgctctca cttgtcttcc 4560

agcggggagc ttcacgttgc cgagtggaag aaccatgacc tccacttgct tccaaggtgc 4620

tagggaagtt tcagggtacg ctggttcccc tctccagctg gaggccgagt ttctggggac 4680

tgcagatttt tctactctgt gatcgattca atgcccgatg cttctgtttc attcccgacc 4740

ctttctacta tgcattttcc ttttatcagg tgtataaagt taaatactgt gtatttatca 4800

ctaaaaagta catgaactta agagacaact aagcctttcg tgtttttcca caggtgttta 4860

agcttctctg tacagttgaa ataaacagac agcaaaatgg tgccaaaaaa aaaaaaaaaa 4920

aaa 4923

<210> SEQ ID NO: 14

<211> LENGTH: 541

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic

<400> SEQENCE: 14

Met Ser Ser Cys Val Ser Ser Gln Pro Ser Ser Asn Arg Ala Ala Pro

1 5 10 15

Gln Asp Glu Leu Gly Gly Arg Gly Ser Ser Ser Ser Glu Ser Gln Lys

20 25 30

Pro Cys Glu Ala Leu Arg Gly Leu Ser Ser Leu Ser Ile His Leu Gly

35 40 45

Met Glu Ser Phe Ile Val Val Thr Glu Cys Glu Pro Gly Cys Ala Val

50 55 60

Asp Leu Gly Leu Ala Arg Asp Arg Pro Leu Glu Ala Asp Gly Gln Glu

65 70 75 80

Val Pro Leu Asp Thr Ser Gly Ser Gln Ala Arg Pro His Leu Ser Gly

85 90 95

Arg Lys Leu Ser Leu Gln Glu Arg Ser Gln Gly Gly Leu Ala Ala Gly

100 105 110

Gly Ser Leu Asp Met Asn Gly Arg Cys Ile Cys Pro Ser Leu Pro Tyr

115 120 125

Ser Pro Val Ser Ser Pro Gln Ser Ser Pro Arg Leu Pro Arg Arg Pro

130 135 140

Thr Val Glu Ser His His Val Ser Ile Thr Gly Met Gln Asp Cys Val

145 150 155 160

Gln Leu Asn Gln Tyr Thr Leu Lys Asp Glu Ile Gly Lys Gly Ser Tyr

165 170 175

Gly Val Val Lys Leu Ala Tyr Asn Glu Asn Asp Asn Thr Tyr Tyr Ala

180 185 190

Met Lys Val Leu Ser Lys Lys Lys Leu Ile Arg Gln Ala Gly Phe Pro

195 200 205

Arg Arg Pro Pro Pro Arg Gly Thr Arg Pro Ala Pro Gly Gly Cys Ile

210 215 220

Gln Pro Arg Gly Pro Ile Glu Gln Val Tyr Gln Glu Ile Ala Ile Leu

225 230 235 240

Lys Lys Leu Asp His Pro Asn Val Val Lys Leu Val Glu Val Leu Asp

245 250 255

Asp Pro Asn Glu Asp His Leu Tyr Met Val Phe Glu Leu Val Asn Gln

260 265 270

Gly Pro Val Met Glu Val Pro Thr Leu Lys Pro Leu Ser Glu Asp Gln

275 280 285

Ala Arg Phe Tyr Phe Gln Asp Leu Ile Lys Gly Ile Glu Tyr Leu His

290 295 300

Tyr Gln Lys Ile Ile His Arg Asp Ile Lys Pro Ser Asn Leu Leu Val

305 310 315 320

Gly Glu Asp Gly His Ile Lys Ile Ala Asp Phe Gly Val Ser Asn Glu

325 330 335

Phe Lys Gly Ser Asp Ala Leu Leu Ser Asn Thr Val Gly Thr Pro Ala

340 345 350

Phe Met Ala Pro Glu Ser Leu Ser Glu Thr Arg Lys Ile Phe Ser Gly

355 360 365

Lys Ala Leu Asp Val Trp Ala Met Gly Val Thr Leu Tyr Cys Phe Val

370 375 380

Phe Gly Gln Cys Pro Phe Met Asp Glu Arg Ile Met Cys Leu His Ser

385 390 395 400

Lys Ile Lys Ser Gln Ala Leu Glu Phe Pro Asp Gln Pro Asp Ile Ala

405 410 415

Glu Asp Leu Lys Asp Leu Ile Thr Arg Met Leu Asp Lys Asn Pro Glu

420 425 430

Ser Arg Ile Val Val Pro Glu Ile Lys Leu His Pro Trp Val Thr Arg

435 440 445

His Gly Ala Glu Pro Leu Pro Ser Glu Asp Glu Asn Cys Thr Leu Val

450 455 460

Glu Val Thr Glu Glu Glu Val Glu Asn Ser Val Lys His Ile Pro Ser

465 470 475 480

Leu Ala Thr Val Ile Leu Val Lys Thr Met Ile Arg Lys Arg Ser Phe

485 490 495

Gly Asn Pro Phe Glu Gly Ser Arg Arg Glu Glu Arg Ser Leu Ser Ala

500 505 510

Pro Gly Asn Leu Leu Thr Lys Gln Gly Ser Glu Asp Asn Leu Gln Gly

515 520 525

Thr Asp Pro Pro Pro Val Gly Glu Glu Glu Val Leu Leu

530 535 540

<210> SEQ ID NO: 15

<211> LENGTH: 3583

<212> TYPE: DNA

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic

<400> SEQENCE: 15

ctgggcccca gcgaggcggt ggggcggggc ggggcggggc ggggcgcgca gcaggagcga 60

gtggggccgc ccgccgggcc gcggacactg tcgcccggcg cccaggttcc caacaaggct 120

acgcagaaga acccccttga ctgaagcaat ggaggggggt ccagctgtct gctgccagga 180

tcctcgggca gagctggtag aacgggtggc agccatcgat gtgactcact tggaggaggc 240

agatggtggc ccagagccta ctagaaacgg tgtggacccc ccaccacggg ccagagctgc 300

ctctgtgatc cctggcagta cttcaagact gctcccagcc cggcctagcc tctcagccag 360

gaagctttcc ctacaggagc ggccagcagg aagctatctg gaggcgcagg ctgggcctta 420

tgccacgggg cctgccagcc acatctcccc ccgggcctgg cggaggccca ccatcgagtc 480

ccaccacgtg gccatctcag atgcagagga ctgcgtgcag ctgaaccagt acaagctgca 540

gagtgagatt ggcaagggtg cctacggtgt ggtgaggctg gcctacaacg aaagtgaaga 600

cagacactat gcaatgaaag tcctttccaa aaagaagtta ctgaagcagt atggctttcc 660

acgtcgccct cccccgagag ggtcccaggc tgcccaggga ggaccagcca agcagctgct 720

gcccctggag cgggtgtacc aggagattgc catcctgaag aagctggacc acgtgaatgt 780

ggtcaaactg atcgaggtcc tggatgaccc agctgaggac aacctctatt tggtgtttga 840

cctcctgaga aaggggcccg tcatggaagt gccctgtgac aagcccttct cggaggagca 900

agctcgcctc tacctgcggg acgtcatcct gggcctcgag tacttgcact gccagaagat 960

cgtccacagg gacatcaagc catccaacct gctcctgggg gatgatgggc acgtgaagat 1020

cgccgacttt ggcgtcagca accagtttga ggggaacgac gctcagctgt ccagcacggc 1080

gggaacccca gcattcatgg cccccgaggc catttctgat tccggccaga gcttcagtgg 1140

gaaggccttg gatgtatggg ccactggcgt cacgttgtac tgctttgtct atgggaagtg 1200

cccattcatc gacgatttca tcctggccct ccacaggaag atcaagaatg agcccgtggt 1260

gtttcctgag gagccagaaa tcagcgagga gctcaaggac ctgatcctga agatgttaga 1320

caagaatccc gagacgagaa ttggggtgcc agacatcaag ttgcaccctt gggtgaccaa 1380

gaacggggag gagccccttc cttcggagga ggagcactgc agcgtggtgg aggtgacaga 1440

ggaggaggtt aagaactcag tcaggctcat ccccagctgg accacggtga tcctggtgaa 1500

gtccatgctg aggaagcgtt cctttgggaa cccgtttgag ccccaagcac ggagggaaga 1560

gcgatccatg tctgctccag gaaacctact ggtgaaagaa gggtttggtg aagggggcaa 1620

gagcccagag ctccccggcg tccaggaaga cgaggctgca tcctgagccc ctgcatgcac 1680

ccagggccac ccggcagcac actcatcccg cgcctccaga ggcccacccc tcatgcaaca 1740

gccgcccccg caggcagggg gctggggact gcagccccac tcccgcccct cccccatcgt 1800

gctgcatgac ctccacgcac gcacgtccag ggacagactg gaatgtatgt catttggggt 1860

cttgggggca gggctcccac gaggccatcc tcctcttctt ggacctcctt ggcctgaccc 1920

attctgtggg gaaaccgggt gcccatggag cctcagaaat gccacccggc tggttggcat 1980

ggcctggggc aggaggcaga ggcaggagac caagatggca ggtggaggcc aggcttacca 2040

caacggaaga gacctcccgc tggggccggg caggcctggc tcagctgcca caggcatatg 2100

gtggagaggg gggtaccctg cccaccttgg ggtggtggca ccagagctct tgtctattca 2160

gacgctggta tgggggctcg gacccctcac tggggacagg gccagtgttg gagaattctg 2220

attccttttt tgttgtcttt tacttttgtt tttaacctgg gggttcgggg agaggccctg 2280

cttgggaaca tctcacgagc tttcctacat cttccgtggt tcccagcaca gcccaagatt 2340

atttggcagc caagtggatg gaactaactt tcctggactg tgtttcgcat tcggcgttat 2400

ctggaaagtg gactgaacgg aatcaagctc tgagcagagg cctgaagcgg aagcaccaca 2460

tcgtccctgc ccatctcact ctctcccttg atgatgcccc tagagctgag gctggagaag 2520

acaccagggc tgactttgac cgagggccat ggacgcgaca ggcctgtggc cctgcgcatg 2580

ctgaaataac tggaacccag cctctcctcc tacaccggcc tacccatctg ggcccaagag 2640

ctgcactcac actcctacaa cgaaggacaa actgtccagg tcggagggat cacgagacac 2700

agaacctgga ggggtgtgca cgctggcagg tggcctctgc ggcaattgcc tcaccctgag 2760

gacatcagca gtcagcctgc tcagagcggg ggtgctggag cgcgtgcaga cacagctctt 2820

ccggagcagc cttcaccttc tctctgggat cagtgtccgg ctggccgacg tggcatttgc 2880

tgaccgaatg ctcatagagg ttgaccccca cagggtcacg caggactcgg acactgccct 2940

ggaaacatgg atggacaagg gcttttggcc acaggtgtgg gtgtcctgtt ggaggagggc 3000

ttgtttggag aagggaggct ggctggggga gaaacccgga tcccgctgca tctccgcgcc 3060

tgtgggtgca tgtcgcgtgc tcatctgttg cacacagctc actcgtatgt cctgcactgg 3120

tacatgcatc tgtaatacag tttctacgtc tatttaaggc taggagccga atgtgcccca 3180

ttgtcagtgg gtccacgttt ctccccggct cctctgggct aaggcagtgt ggcccgaagc 3240

ttaaaaagtt actcggtact gtttttaaga acacttttat agagttagtg gaaggcaagt 3300

taagagccaa tcactgatcc ccaagtgttt cttgagcatc tggtctgggg ggaccacttt 3360

gatcggaccc acccttggaa agctcagggg taggcccagg tgggatgctc accctgtcac 3420

tgagggtttt ggttggcatc gttgtttttg aatgtagcac aagcgatgag caaactctat 3480

aagagtgttt taaaaattaa cttcccagga agtgagttaa aaacaataaa agccctttct 3540

tgagttaaaa agaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaa 3583

<210> SEQ ID NO: 16

<211> LENGTH: 505

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic

<400> SEQENCE: 16

Met Glu Gly Gly Pro Ala Val Cys Cys Gln Asp Pro Arg Ala Glu Leu

1 5 10 15

Val Glu Arg Val Ala Ala Ile Asp Val Thr His Leu Glu Glu Ala Asp

20 25 30

Gly Gly Pro Glu Pro Thr Arg Asn Gly Val Asp Pro Pro Pro Arg Ala

35 40 45

Arg Ala Ala Ser Val Ile Pro Gly Ser Thr Ser Arg Leu Leu Pro Ala

50 55 60

Arg Pro Ser Leu Ser Ala Arg Lys Leu Ser Leu Gln Glu Arg Pro Ala

65 70 75 80

Gly Ser Tyr Leu Glu Ala Gln Ala Gly Pro Tyr Ala Thr Gly Pro Ala

85 90 95

Ser His Ile Ser Pro Arg Ala Trp Arg Arg Pro Thr Ile Glu Ser His

100 105 110

His Val Ala Ile Ser Asp Ala Glu Asp Cys Val Gln Leu Asn Gln Tyr

115 120 125

Lys Leu Gln Ser Glu Ile Gly Lys Gly Ala Tyr Gly Val Val Arg Leu

130 135 140

Ala Tyr Asn Glu Ser Glu Asp Arg His Tyr Ala Met Lys Val Leu Ser

145 150 155 160

Lys Lys Lys Leu Leu Lys Gln Tyr Gly Phe Pro Arg Arg Pro Pro Pro

165 170 175

Arg Gly Ser Gln Ala Ala Gln Gly Gly Pro Ala Lys Gln Leu Leu Pro

180 185 190

Leu Glu Arg Val Tyr Gln Glu Ile Ala Ile Leu Lys Lys Leu Asp His

195 200 205

Val Asn Val Val Lys Leu Ile Glu Val Leu Asp Asp Pro Ala Glu Asp

210 215 220

Asn Leu Tyr Leu Val Phe Asp Leu Leu Arg Lys Gly Pro Val Met Glu

225 230 235 240

Val Pro Cys Asp Lys Pro Phe Ser Glu Glu Gln Ala Arg Leu Tyr Leu

245 250 255

Arg Asp Val Ile Leu Gly Leu Glu Tyr Leu His Cys Gln Lys Ile Val

260 265 270

His Arg Asp Ile Lys Pro Ser Asn Leu Leu Leu Gly Asp Asp Gly His

275 280 285

Val Lys Ile Ala Asp Phe Gly Val Ser Asn Gln Phe Glu Gly Asn Asp

290 295 300

Ala Gln Leu Ser Ser Thr Ala Gly Thr Pro Ala Phe Met Ala Pro Glu

305 310 315 320

Ala Ile Ser Asp Ser Gly Gln Ser Phe Ser Gly Lys Ala Leu Asp Val

325 330 335

Trp Ala Thr Gly Val Thr Leu Tyr Cys Phe Val Tyr Gly Lys Cys Pro

340 345 350

Phe Ile Asp Asp Phe Ile Leu Ala Leu His Arg Lys Ile Lys Asn Glu

355 360 365

Pro Val Val Phe Pro Glu Glu Pro Glu Ile Ser Glu Glu Leu Lys Asp

370 375 380

Leu Ile Leu Lys Met Leu Asp Lys Asn Pro Glu Thr Arg Ile Gly Val

385 390 395 400

Pro Asp Ile Lys Leu His Pro Trp Val Thr Lys Asn Gly Glu Glu Pro

405 410 415

Leu Pro Ser Glu Glu Glu His Cys Ser Val Val Glu Val Thr Glu Glu

420 425 430

Glu Val Lys Asn Ser Val Arg Leu Ile Pro Ser Trp Thr Thr Val Ile

435 440 445

Leu Val Lys Ser Met Leu Arg Lys Arg Ser Phe Gly Asn Pro Phe Glu

450 455 460

Pro Gln Ala Arg Arg Glu Glu Arg Ser Met Ser Ala Pro Gly Asn Leu

465 470 475 480

Leu Val Lys Glu Gly Phe Gly Glu Gly Gly Lys Ser Pro Glu Leu Pro

485 490 495

Gly Val Gln Glu Asp Glu Ala Ala Ser

500 505

<210> SEQ ID NO: 17

<211> LENGTH: 3529

<212> TYPE: DNA

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic

<400> SEQENCE: 17

agcagaacag agtatgcaat ttgggaagct gtggtgtggc tgcagtggag agttcccaac 60

aaggctacgc agaagaaccc ccttgactga agcaatggag gggggtccag ctgtctgctg 120

ccaggatcct cgggcagagc tggtagaacg ggtggcagcc atcgatgtga ctcacttgga 180

ggaggcagat ggtggcccag agcctactag aaacggtgtg gaccccccac cacgggccag 240

agctgcctct gtgatccctg gcagtacttc aagactgctc ccagcccggc ctagcctctc 300

agccaggaag ctttccctac aggagcggcc agcaggaagc tatctggagg cgcaggctgg 360

gccttatgcc acggggcctg ccagccacat ctccccccgg gcctggcgga ggcccaccat 420

cgagtcccac cacgtggcca tctcagatgc agaggactgc gtgcagctga accagtacaa 480

gctgcagagt gagattggca agggtgccta cggtgtggtg aggctggcct acaacgaaag 540

tgaagacaga cactatgcaa tgaaagtcct ttccaaaaag aagttactga agcagtatgg 600

ctttccacgt cgccctcccc cgagagggtc ccaggctgcc cagggaggac cagccaagca 660

gctgctgccc ctggagcggg tgtaccagga gattgccatc ctgaagaagc tggaccacgt 720

gaatgtggtc aaactgatcg aggtcctgga tgacccagct gaggacaacc tctatttggt 780

gtttgacctc ctgagaaagg ggcccgtcat ggaagtgccc tgtgacaagc ccttctcgga 840

ggagcaagct cgcctctacc tgcgggacgt catcctgggc ctcgagtact tgcactgcca 900

gaagatcgtc cacagggaca tcaagccatc caacctgctc ctgggggatg atgggcacgt 960

gaagatcgcc gactttggcg tcagcaacca gtttgagggg aacgacgctc agctgtccag 1020

cacggcggga accccagcat tcatggcccc cgaggccatt tctgattccg gccagagctt 1080

cagtgggaag gccttggatg tatgggccac tggcgtcacg ttgtactgct ttgtctatgg 1140

gaagtgccca ttcatcgacg atttcatcct ggccctccac aggaagatca agaatgagcc 1200

cgtggtgttt cctgaggagc cagaaatcag cgaggagctc aaggacctga tcctgaagat 1260

gttagacaag aatcccgaga cgagaattgg ggtgccagac atcaagttgc acccttgggt 1320

gaccaagaac ggggaggagc cccttccttc ggaggaggag cactgcagcg tggtggaggt 1380

gacagaggag gaggttaaga actcagtcag gctcatcccc agctggacca cggtgatcct 1440

ggtgaagtcc atgctgagga agcgttcctt tgggaacccg tttgagcccc aagcacggag 1500

ggaagagcga tccatgtctg ctccaggaaa cctactggtg aaagaagggt ttggtgaagg 1560

gggcaagagc ccagagctcc ccggcgtcca ggaagacgag gctgcatcct gagcccctgc 1620

atgcacccag ggccacccgg cagcacactc atcccgcgcc tccagaggcc cacccctcat 1680

gcaacagccg cccccgcagg cagggggctg gggactgcag ccccactccc gcccctcccc 1740

catcgtgctg catgacctcc acgcacgcac gtccagggac agactggaat gtatgtcatt 1800

tggggtcttg ggggcagggc tcccacgagg ccatcctcct cttcttggac ctccttggcc 1860

tgacccattc tgtggggaaa ccgggtgccc atggagcctc agaaatgcca cccggctggt 1920

tggcatggcc tggggcagga ggcagaggca ggagaccaag atggcaggtg gaggccaggc 1980

ttaccacaac ggaagagacc tcccgctggg gccgggcagg cctggctcag ctgccacagg 2040

catatggtgg agaggggggt accctgccca ccttggggtg gtggcaccag agctcttgtc 2100

tattcagacg ctggtatggg ggctcggacc cctcactggg gacagggcca gtgttggaga 2160

attctgattc cttttttgtt gtcttttact tttgttttta acctgggggt tcggggagag 2220

gccctgcttg ggaacatctc acgagctttc ctacatcttc cgtggttccc agcacagccc 2280

aagattattt ggcagccaag tggatggaac taactttcct ggactgtgtt tcgcattcgg 2340

cgttatctgg aaagtggact gaacggaatc aagctctgag cagaggcctg aagcggaagc 2400

accacatcgt ccctgcccat ctcactctct cccttgatga tgcccctaga gctgaggctg 2460

gagaagacac cagggctgac tttgaccgag ggccatggac gcgacaggcc tgtggccctg 2520

cgcatgctga aataactgga acccagcctc tcctcctaca ccggcctacc catctgggcc 2580

caagagctgc actcacactc ctacaacgaa ggacaaactg tccaggtcgg agggatcacg 2640

agacacagaa cctggagggg tgtgcacgct ggcaggtggc ctctgcggca attgcctcac 2700

cctgaggaca tcagcagtca gcctgctcag agcgggggtg ctggagcgcg tgcagacaca 2760

gctcttccgg agcagccttc accttctctc tgggatcagt gtccggctgg ccgacgtggc 2820

atttgctgac cgaatgctca tagaggttga cccccacagg gtcacgcagg actcggacac 2880

tgccctggaa acatggatgg acaagggctt ttggccacag gtgtgggtgt cctgttggag 2940

gagggcttgt ttggagaagg gaggctggct gggggagaaa cccggatccc gctgcatctc 3000

cgcgcctgtg ggtgcatgtc gcgtgctcat ctgttgcaca cagctcactc gtatgtcctg 3060

cactggtaca tgcatctgta atacagtttc tacgtctatt taaggctagg agccgaatgt 3120

gccccattgt cagtgggtcc acgtttctcc ccggctcctc tgggctaagg cagtgtggcc 3180

cgaagcttaa aaagttactc ggtactgttt ttaagaacac ttttatagag ttagtggaag 3240

gcaagttaag agccaatcac tgatccccaa gtgtttcttg agcatctggt ctggggggac 3300

cactttgatc ggacccaccc ttggaaagct caggggtagg cccaggtggg atgctcaccc 3360

tgtcactgag ggttttggtt ggcatcgttg tttttgaatg tagcacaagc gatgagcaaa 3420

ctctataaga gtgttttaaa aattaacttc ccaggaagtg agttaaaaac aataaaagcc 3480

ctttcttgag ttaaaaagaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaa 3529

<210> SEQ ID NO: 18

<211> LENGTH: 505

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic

<400> SEQENCE: 18

Met Glu Gly Gly Pro Ala Val Cys Cys Gln Asp Pro Arg Ala Glu Leu

1 5 10 15

Val Glu Arg Val Ala Ala Ile Asp Val Thr His Leu Glu Glu Ala Asp

20 25 30

Gly Gly Pro Glu Pro Thr Arg Asn Gly Val Asp Pro Pro Pro Arg Ala

35 40 45

Arg Ala Ala Ser Val Ile Pro Gly Ser Thr Ser Arg Leu Leu Pro Ala

50 55 60

Arg Pro Ser Leu Ser Ala Arg Lys Leu Ser Leu Gln Glu Arg Pro Ala

65 70 75 80

Gly Ser Tyr Leu Glu Ala Gln Ala Gly Pro Tyr Ala Thr Gly Pro Ala

85 90 95

Ser His Ile Ser Pro Arg Ala Trp Arg Arg Pro Thr Ile Glu Ser His

100 105 110

His Val Ala Ile Ser Asp Ala Glu Asp Cys Val Gln Leu Asn Gln Tyr

115 120 125

Lys Leu Gln Ser Glu Ile Gly Lys Gly Ala Tyr Gly Val Val Arg Leu

130 135 140

Ala Tyr Asn Glu Ser Glu Asp Arg His Tyr Ala Met Lys Val Leu Ser

145 150 155 160

Lys Lys Lys Leu Leu Lys Gln Tyr Gly Phe Pro Arg Arg Pro Pro Pro

165 170 175

Arg Gly Ser Gln Ala Ala Gln Gly Gly Pro Ala Lys Gln Leu Leu Pro

180 185 190

Leu Glu Arg Val Tyr Gln Glu Ile Ala Ile Leu Lys Lys Leu Asp His

195 200 205

Val Asn Val Val Lys Leu Ile Glu Val Leu Asp Asp Pro Ala Glu Asp

210 215 220

Asn Leu Tyr Leu Val Phe Asp Leu Leu Arg Lys Gly Pro Val Met Glu

225 230 235 240

Val Pro Cys Asp Lys Pro Phe Ser Glu Glu Gln Ala Arg Leu Tyr Leu

245 250 255

Arg Asp Val Ile Leu Gly Leu Glu Tyr Leu His Cys Gln Lys Ile Val

260 265 270

His Arg Asp Ile Lys Pro Ser Asn Leu Leu Leu Gly Asp Asp Gly His

275 280 285

Val Lys Ile Ala Asp Phe Gly Val Ser Asn Gln Phe Glu Gly Asn Asp

290 295 300

Ala Gln Leu Ser Ser Thr Ala Gly Thr Pro Ala Phe Met Ala Pro Glu

305 310 315 320

Ala Ile Ser Asp Ser Gly Gln Ser Phe Ser Gly Lys Ala Leu Asp Val

325 330 335

Trp Ala Thr Gly Val Thr Leu Tyr Cys Phe Val Tyr Gly Lys Cys Pro

340 345 350

Phe Ile Asp Asp Phe Ile Leu Ala Leu His Arg Lys Ile Lys Asn Glu

355 360 365

Pro Val Val Phe Pro Glu Glu Pro Glu Ile Ser Glu Glu Leu Lys Asp

370 375 380

Leu Ile Leu Lys Met Leu Asp Lys Asn Pro Glu Thr Arg Ile Gly Val

385 390 395 400

Pro Asp Ile Lys Leu His Pro Trp Val Thr Lys Asn Gly Glu Glu Pro

405 410 415

Leu Pro Ser Glu Glu Glu His Cys Ser Val Val Glu Val Thr Glu Glu

420 425 430

Glu Val Lys Asn Ser Val Arg Leu Ile Pro Ser Trp Thr Thr Val Ile

435 440 445

Leu Val Lys Ser Met Leu Arg Lys Arg Ser Phe Gly Asn Pro Phe Glu

450 455 460

Pro Gln Ala Arg Arg Glu Glu Arg Ser Met Ser Ala Pro Gly Asn Leu

465 470 475 480

Leu Val Lys Glu Gly Phe Gly Glu Gly Gly Lys Ser Pro Glu Leu Pro

485 490 495

Gly Val Gln Glu Asp Glu Ala Ala Ser

500 505

<210> SEQ ID NO: 19

<211> LENGTH: 2535

<212> TYPE: DNA

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic

<400> SEQENCE: 19

ctgggcccca gcgaggcggt ggggcggggc ggggcggggc ggggcgcgca gcaggagcga 60

gtggggccgc ccgccgggcc gcggacactg tcgcccggcg cccaggttcc caacaaggct 120

acgcagaaga acccccttga ctgaagcaat ggaggggggt ccagctgtct gctgccagga 180

tcctcgggca gagctggtag aacgggtggc agccatcgat gtgactcact tggaggaggc 240

agatggtggc ccagagccta ctagaaacgg tgtggacccc ccaccacggg ccagagctgc 300

ctctgtgatc cctggcagta cttcaagact gctcccagcc cggcctagcc tctcagccag 360

gaagctttcc ctacaggagc ggccagcagg aagctatctg gaggcgcagg ctgggcctta 420

tgccacgggg cctgccagcc acatctcccc ccgggcctgg cggaggccca ccatcgagtc 480

ccaccacgtg gccatctcag atgcagagga ctgcgtgcag ctgaaccagt acaagctgca 540

gagtgagatt ggcaagggtg cctacggtgt ggtgaggctg gcctacaacg aaagtgaaga 600

cagacactat gcaatgaaag tcctttccaa aaagaagtta ctgaagcagt atggctttcc 660

acgtcgccct cccccgagag ggtcccaggc tgcccaggga ggaccagcca agcagctgct 720

gcccctggag cgggtgtacc aggagattgc catcctgaag aagctggacc acgtgaatgt 780

ggtcaaactg atcgaggtcc tggatgaccc agctgaggac aacctctatt tggccctgca 840

gaaccaggcc cagaatatcc agttagattc aacaaatatc gccaagcccc actccctgct 900

tccctctgag cagcaagaca gtggatccac gtgggctgcg cgctcagtgt ttgacctcct 960

gagaaagggg cccgtcatgg aagtgccctg tgacaagccc ttctcggagg agcaagctcg 1020

cctctacctg cgggacgtca tcctgggcct cgagtacttg cactgccaga agatcgtcca 1080

cagggacatc aagccatcca acctgctcct gggggatgat gggcacgtga agatcgccga 1140

ctttggcgtc agcaaccagt ttgaggggaa cgacgctcag ctgtccagca cggcgggaac 1200

cccagcattc atggcccccg aggccatttc tgattccggc cagagcttca gtgggaaggc 1260

cttggatgta tgggccactg gcgtcacgtt gtactgcttt gtctatggga agtgcccatt 1320

catcgacgat ttcatcctgg ccctccacag gaagatcaag aatgagcccg tggtgtttcc 1380

tgaggagcca gaaatcagcg aggagctcaa ggacctgatc ctgaagatgt tagacaagaa 1440

tcccgagacg agaattgggg tgccagacat caagttgcac ccttgggtga ccaagaacgg 1500

ggaggagccc cttccttcgg aggaggagca ctgcagcgtg gtggaggtga cagaggagga 1560

ggttaagaac tcagtcaggc tcatccccag ctggaccacg gtgatcctgg tgaagtccat 1620

gctgaggaag cgttcctttg ggaacccgtt tgagccccaa gcacggaggg aagagcgatc 1680

catgtctgct ccaggaaacc tactggtgta agtactggtg ggccagggac tgccgggcac 1740

tccctggagt tgggtgggga ggtctgaggc ccatcctccc actctcactg tcgttgggcc 1800

aaggccagag cctggggact tggccaggtc tcggtgttgg ccccatttgc atctctgtcc 1860

ccaaggttag tcggggctag aagggacctt ttgggcccag ctcttgcttc attcctgggg 1920

ccagcatccc tcacacacac acttccaggg atgaggagct cacgcagccc ctccatggga 1980

caggaagacc cttcttccat gcagcttgat gtcactctct cactgggtcc agcccctctg 2040

gggcttcaaa tctgtggccc cctcagccct tggcagcctg gcagaggttt gcagacaggc 2100

tgatgttggc ttcctgtagg aggctggcgg gctgtagagg aggggtgctg gcccctctgc 2160

ctggccctgg ggactgttgg ctgctctccc aagtggccca ggctgcctgc agccattgct 2220

ggggctctgt gcccagtcag cactttgtga gtgcttgttc agtgagtaag cagggacagg 2280

ctggccggtg gaccacggga gaggaacccg cattggccga gggctcccta tggtgagcca 2340

cgcctgtggg ttcaccacct cctaggaggg tccagaaaag cagctcccca agcctgtgcg 2400

cctcgtcctc agcagatcca ccttcttcac tataataaaa gccagtctgg gatgctaaaa 2460

aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa 2520

aaaaaaaaaa aaaaa 2535

<210> SEQ ID NO: 20

<211> LENGTH: 520

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic

<400> SEQENCE: 20

Met Glu Gly Gly Pro Ala Val Cys Cys Gln Asp Pro Arg Ala Glu Leu

1 5 10 15

Val Glu Arg Val Ala Ala Ile Asp Val Thr His Leu Glu Glu Ala Asp

20 25 30

Gly Gly Pro Glu Pro Thr Arg Asn Gly Val Asp Pro Pro Pro Arg Ala

35 40 45

Arg Ala Ala Ser Val Ile Pro Gly Ser Thr Ser Arg Leu Leu Pro Ala

50 55 60

Arg Pro Ser Leu Ser Ala Arg Lys Leu Ser Leu Gln Glu Arg Pro Ala

65 70 75 80

Gly Ser Tyr Leu Glu Ala Gln Ala Gly Pro Tyr Ala Thr Gly Pro Ala

85 90 95

Ser His Ile Ser Pro Arg Ala Trp Arg Arg Pro Thr Ile Glu Ser His

100 105 110

His Val Ala Ile Ser Asp Ala Glu Asp Cys Val Gln Leu Asn Gln Tyr

115 120 125

Lys Leu Gln Ser Glu Ile Gly Lys Gly Ala Tyr Gly Val Val Arg Leu

130 135 140

Ala Tyr Asn Glu Ser Glu Asp Arg His Tyr Ala Met Lys Val Leu Ser

145 150 155 160

Lys Lys Lys Leu Leu Lys Gln Tyr Gly Phe Pro Arg Arg Pro Pro Pro

165 170 175

Arg Gly Ser Gln Ala Ala Gln Gly Gly Pro Ala Lys Gln Leu Leu Pro

180 185 190

Leu Glu Arg Val Tyr Gln Glu Ile Ala Ile Leu Lys Lys Leu Asp His

195 200 205

Val Asn Val Val Lys Leu Ile Glu Val Leu Asp Asp Pro Ala Glu Asp

210 215 220

Asn Leu Tyr Leu Ala Leu Gln Asn Gln Ala Gln Asn Ile Gln Leu Asp

225 230 235 240

Ser Thr Asn Ile Ala Lys Pro His Ser Leu Leu Pro Ser Glu Gln Gln

245 250 255

Asp Ser Gly Ser Thr Trp Ala Ala Arg Ser Val Phe Asp Leu Leu Arg

260 265 270

Lys Gly Pro Val Met Glu Val Pro Cys Asp Lys Pro Phe Ser Glu Glu

275 280 285

Gln Ala Arg Leu Tyr Leu Arg Asp Val Ile Leu Gly Leu Glu Tyr Leu

290 295 300

His Cys Gln Lys Ile Val His Arg Asp Ile Lys Pro Ser Asn Leu Leu

305 310 315 320

Leu Gly Asp Asp Gly His Val Lys Ile Ala Asp Phe Gly Val Ser Asn

325 330 335

Gln Phe Glu Gly Asn Asp Ala Gln Leu Ser Ser Thr Ala Gly Thr Pro

340 345 350

Ala Phe Met Ala Pro Glu Ala Ile Ser Asp Ser Gly Gln Ser Phe Ser

355 360 365

Gly Lys Ala Leu Asp Val Trp Ala Thr Gly Val Thr Leu Tyr Cys Phe

370 375 380

Val Tyr Gly Lys Cys Pro Phe Ile Asp Asp Phe Ile Leu Ala Leu His

385 390 395 400

Arg Lys Ile Lys Asn Glu Pro Val Val Phe Pro Glu Glu Pro Glu Ile

405 410 415

Ser Glu Glu Leu Lys Asp Leu Ile Leu Lys Met Leu Asp Lys Asn Pro

420 425 430

Glu Thr Arg Ile Gly Val Pro Asp Ile Lys Leu His Pro Trp Val Thr

435 440 445

Lys Asn Gly Glu Glu Pro Leu Pro Ser Glu Glu Glu His Cys Ser Val

450 455 460

Val Glu Val Thr Glu Glu Glu Val Lys Asn Ser Val Arg Leu Ile Pro

465 470 475 480

Ser Trp Thr Thr Val Ile Leu Val Lys Ser Met Leu Arg Lys Arg Ser

485 490 495

Phe Gly Asn Pro Phe Glu Pro Gln Ala Arg Arg Glu Glu Arg Ser Met

500 505 510

Ser Ala Pro Gly Asn Leu Leu Val

515 520

<210> SEQ ID NO: 21

<211> LENGTH: 5085

<212> TYPE: DNA

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic

<400> SEQENCE: 21

agcgccatgc gcagactcag ttcctggaga aagatggcga cagccgagaa gcagaaacac 60

gacgggcggg tgaagatcgg ccactacatt ctgggtgaca cgctgggggt cggcaccttc 120

ggcaaagtga aggttggcaa acatgaattg actgggcata aagtagctgt gaagatactc 180

aatcgacaga agattcggag ccttgatgtg gtaggaaaaa tccgcagaga aattcagaac 240

ctcaagcttt tcaggcatcc tcatataatt aaactgtacc aggtcatcag tacaccatct 300

gatattttca tggtgatgga atatgtctca ggaggagagc tatttgatta tatctgtaag 360

aatggaaggc tggatgaaaa agaaagtcgg cgtctgttcc aacagatcct ttctggtgtg 420

gattattgtc acaggcatat ggtggtccat agagatttga aacctgaaaa tgtcctgctt 480

gatgcacaca tgaatgcaaa gatagctgat tttggtcttt caaacatgat gtcagatggt 540

gaatttttaa gaacaagttg tggctcaccc aactatgctg caccagaagt aatttcagga 600

agattgtatg caggcccaga ggtagatata tggagcagtg gggttattct ctatgcttta 660

ttatgtggaa cccttccatt tgatgatgac catgtgccaa ctctttttaa gaagatatgt 720

gatgggatct tctatacccc tcaatattta aatccttctg tgattagcct tttgaaacat 780

atgctgcagg tggatcccat gaagagggcc acaatcaaag atatcaggga acatgaatgg 840

tttaaacagg accttccaaa atatctcttt cctgaggatc catcatatag ttcaaccatg 900

attgatgatg aagccttaaa agaagtatgt gaaaagtttg agtgctcaga agaggaagtt 960

ctcagctgtc tttacaacag aaatcaccag gatcctttgg cagttgccta ccatctcata 1020

atagataaca ggagaataat gaatgaagcc aaagatttct atttggcgac aagcccacct 1080

gattcttttc ttgatgatca tcacctgact cggccccatc ctgaaagagt accattcttg 1140

gttgctgaaa caccaagggc acgccatacc cttgatgaat taaatccaca gaaatccaaa 1200

caccaaggtg taaggaaagc aaaatggcat ttaggaatta gaagtcaaag tcgaccaaat 1260

gatattatgg cagaagtatg tagagcaatc aaacaattgg attatgaatg gaaggttgta 1320

aacccatatt atttgcgtgt acgaaggaag aatcctgtga caagcactta ctccaaaatg 1380

agtctacagt tataccaagt ggatagtaga acttatctac tggatttccg tagtattgat 1440

gatgaaatta cagaagccaa atcagggact gctactccac agagatcggg atcagttagc 1500

aactatcgat cttgccaaag gagtgattca gatgctgagg ctcaaggaaa atcctcagaa 1560

gtttctctta cctcatctgt gacctcactt gactcttctc ctgttgacct aactccaaga 1620

cctggaagtc acacaataga attttttgag atgtgtgcaa atctaattaa aattcttgca 1680

caataaacag aaaactttgc ttatttcttt tgcagcaata agcatgcata ataagtcaca 1740

gccaaatgct tccatttgta atcaagttat acataattat aaccgagggc tggcgttttg 1800

gaatgcaatt tgcacaggga ttggaacatg atttatagtt aaaagcctaa tatgcagaaa 1860

tgaattaaga tcattttgtt gttcattgtg cagtatgtat atagcataat atacacagtg 1920

aattataggt ctcaggctta cttgattttt ggctatttta tatttagtgt acacagggct 1980

ttgaaatatt aatttacata aaggccttca tatattatta cgtgttatat attacgtgtt 2040

ataaatttat tcaataaata tttgcctaga attcccaaga cctttatagg tgattttgtt 2100

ttctgggctc cttaacttca taaatagcta gtatcttcca gcagtagtaa cagtctggat 2160

aacttcttcc atatccctcc ctctttgttt ttttgagaca gtgtcacttt gtcacccagg 2220

ctggagtgca atggtgtggt ctcggctcac tgcaacctcc acctcccggg ttcaagtgat 2280

tctcccgcct cagcttcctg agtagctgga actacaggcg tgtgccacca cacccggcta 2340

atttttcgta tttttagtgt agacggggtt tcactatgtt gcccaggctg gtctcgaact 2400

cctgaccgcg tgatccacca cctcagcttc ccaaagtggt gggattacag gcgtgagcca 2460

ccgcacccgg cctccatatc ccccttttaa aattctgtag tgtatggtaa gtcatatcag 2520

atatcagacc taatttaaat ttcattttag ctttacaagt ccaaaaacac agaatttata 2580

tattcagata ctctagcact aattttagtc ttaaaatatt cccacgatat tctgtacaca 2640

aaatgttctt tttgttacaa gagctgagtt gcatatactg tagataaatc atattatttt 2700

tgccaatttc acaaattcct ctggcccatc atgtcagtca ttattgagta tatgcacaca 2760

ttgctactta tttgattatg tatcttttaa attgattcag tgcatagaaa actatctctt 2820

acaaacttta agtgctctga tatgacttcc cccccaaatt ttattatgaa catttttaaa 2880

aacagaaaaa ttgaaaaact gtttggtaag cacatgtata tctaccattt agattcagca 2940

gttgttaatg ttttgtcatt tgttttctct atacctatat atgtatagat acagctagtt 3000

atgcatatat atgcatatat gtgtttgttt gtgtatgtat atatgctttt ttccccctga 3060

accatttgga tgttacagac atacttatca ccgtgaaaat acttcaagta tctcctacag 3120

ataatgacat tctcctaaaa atccgtaata ccattgtaaa agtaataatt ccccaatatc 3180

atctaatcaa gccatattta aatttctgaa gttaactcca aatttcttta tagctgatta 3240

tttcaaacta ggatccaatt aaagtttaca tatgacactt ggttataact ctttagttgg 3300

atataacatt attattattt tgataaaata tggaacaaat caattctatt aataagtggt 3360

cacatttgtt ttgggcttaa attacttttt aaagatactg gattttccta agatttctga 3420

tttacactga tatttttttt tgtcattctt aattgcatca cacaatagat gtaaatgaag 3480

atgtagtcac ctcagataaa attggtatcg tgtatgataa tattgtatca tttatatttg 3540

ccttatgtta actttaagaa attgattttt ttgtattaat cattttccca ttgcaacaga 3600

gctatatttt ttctatttta agaatcatat tttaggatta tttttggcaa atacagtgag 3660

cacttatgta accagatgat aatgaactca aatgtcatga tagcttgcat aaatggtgac 3720

tctagtagat ttgactcaag cacttctaga atcatgcact gaattcaaaa gaaaaatctt 3780

gctgcttttt gtccagggct tgttctattc aacttctaat ttgaaagctg tacaaagtaa 3840

tagaagttcc atttaaatat gagttcaaaa ctgtatttac tttttatgtg gccctctctt 3900

taggggattc taattttact tagggtctct aagtgcagca taatgttcct gatgttaaca 3960

gaagactgta tttttaaagt tacaaatttg tatatggaat taagtaatgg cgctatatac 4020

gctgttgtgg ggagggggga agaaaaggag gaaccaatta aataggacct tttaaaaatt 4080

gttaattttg taaactttgc ttctcttata agttattgtg attcatttta gttactgtgt 4140

tttattttga aaatatttaa atattgcact tctataaata gtatgataaa tgcacagaca 4200

attgcagtaa attctttttt aagctaggat atttgaaatg acaacctttg gttaagtgtg 4260

tcaaggttgc aacagaattt tcacaatttt tttgttgttt gcaaattgtt actaatattg 4320

aagaggtaag ggaggcaatg caaatgattt ttaatctttt tttattatct tttcagcagt 4380

ttatattttt tgtgacttta tgcaaccata tttttacttt gtcttgacaa ctgaaagatg 4440

tataaggttt tttgccagaa atgtactgta tacatagttt taagtataac agattttact 4500

gatatgtaaa aattttgcca ttaaaataaa tgatttctca ctgagaggaa cttttctacc 4560

aggttggggc atatgggagc ttaatatatc atatctaatt taaaataatt tcactgaaat 4620

aaactccatt gcttttacct aatttttttc ttgagatgct tttgtagttt ttcagagttt 4680

tagatgattt tatacaaaat cctctgccta gcactgctct ttttgatgtt gtagtgacac 4740

catttacatt gaattaatgc ttggtagcct ggggctagat gtggaactcc atggatctgt 4800

gttctgactg gcacctttgg aatgaaagaa aagtgtgtgc tgtccaaatt ttttcccctt 4860

aattctttcc ctcatcttct cacccataat agaaatttta tttccattgt gagttctgac 4920

aagaatgaaa ttccacatac aacataactg taaattgttg gtaggtagaa gttaatattt 4980

gtggttcatg tatattttga ccagagtata tttaagtata taatttcagc ttccttgatt 5040

tagaaatatg atataataaa gaaaaactcc atttatcatc tgtta 5085

<210> SEQ ID NO: 22

<211> LENGTH: 559

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic

<400> SEQENCE: 22

Met Arg Arg Leu Ser Ser Trp Arg Lys Met Ala Thr Ala Glu Lys Gln

1 5 10 15

Lys His Asp Gly Arg Val Lys Ile Gly His Tyr Ile Leu Gly Asp Thr

20 25 30

Leu Gly Val Gly Thr Phe Gly Lys Val Lys Val Gly Lys His Glu Leu

35 40 45

Thr Gly His Lys Val Ala Val Lys Ile Leu Asn Arg Gln Lys Ile Arg

50 55 60

Ser Leu Asp Val Val Gly Lys Ile Arg Arg Glu Ile Gln Asn Leu Lys

65 70 75 80

Leu Phe Arg His Pro His Ile Ile Lys Leu Tyr Gln Val Ile Ser Thr

85 90 95

Pro Ser Asp Ile Phe Met Val Met Glu Tyr Val Ser Gly Gly Glu Leu

100 105 110

Phe Asp Tyr Ile Cys Lys Asn Gly Arg Leu Asp Glu Lys Glu Ser Arg

115 120 125

Arg Leu Phe Gln Gln Ile Leu Ser Gly Val Asp Tyr Cys His Arg His

130 135 140

Met Val Val His Arg Asp Leu Lys Pro Glu Asn Val Leu Leu Asp Ala

145 150 155 160

His Met Asn Ala Lys Ile Ala Asp Phe Gly Leu Ser Asn Met Met Ser

165 170 175

Asp Gly Glu Phe Leu Arg Thr Ser Cys Gly Ser Pro Asn Tyr Ala Ala

180 185 190

Pro Glu Val Ile Ser Gly Arg Leu Tyr Ala Gly Pro Glu Val Asp Ile

195 200 205

Trp Ser Ser Gly Val Ile Leu Tyr Ala Leu Leu Cys Gly Thr Leu Pro

210 215 220

Phe Asp Asp Asp His Val Pro Thr Leu Phe Lys Lys Ile Cys Asp Gly

225 230 235 240

Ile Phe Tyr Thr Pro Gln Tyr Leu Asn Pro Ser Val Ile Ser Leu Leu

245 250 255

Lys His Met Leu Gln Val Asp Pro Met Lys Arg Ala Thr Ile Lys Asp

260 265 270

Ile Arg Glu His Glu Trp Phe Lys Gln Asp Leu Pro Lys Tyr Leu Phe

275 280 285

Pro Glu Asp Pro Ser Tyr Ser Ser Thr Met Ile Asp Asp Glu Ala Leu

290 295 300

Lys Glu Val Cys Glu Lys Phe Glu Cys Ser Glu Glu Glu Val Leu Ser

305 310 315 320

Cys Leu Tyr Asn Arg Asn His Gln Asp Pro Leu Ala Val Ala Tyr His

325 330 335

Leu Ile Ile Asp Asn Arg Arg Ile Met Asn Glu Ala Lys Asp Phe Tyr

340 345 350

Leu Ala Thr Ser Pro Pro Asp Ser Phe Leu Asp Asp His His Leu Thr

355 360 365

Arg Pro His Pro Glu Arg Val Pro Phe Leu Val Ala Glu Thr Pro Arg

370 375 380

Ala Arg His Thr Leu Asp Glu Leu Asn Pro Gln Lys Ser Lys His Gln

385 390 395 400

Gly Val Arg Lys Ala Lys Trp His Leu Gly Ile Arg Ser Gln Ser Arg

405 410 415

Pro Asn Asp Ile Met Ala Glu Val Cys Arg Ala Ile Lys Gln Leu Asp

420 425 430

Tyr Glu Trp Lys Val Val Asn Pro Tyr Tyr Leu Arg Val Arg Arg Lys

435 440 445

Asn Pro Val Thr Ser Thr Tyr Ser Lys Met Ser Leu Gln Leu Tyr Gln

450 455 460

Val Asp Ser Arg Thr Tyr Leu Leu Asp Phe Arg Ser Ile Asp Asp Glu

465 470 475 480

Ile Thr Glu Ala Lys Ser Gly Thr Ala Thr Pro Gln Arg Ser Gly Ser

485 490 495

Val Ser Asn Tyr Arg Ser Cys Gln Arg Ser Asp Ser Asp Ala Glu Ala

500 505 510

Gln Gly Lys Ser Ser Glu Val Ser Leu Thr Ser Ser Val Thr Ser Leu

515 520 525

Asp Ser Ser Pro Val Asp Leu Thr Pro Arg Pro Gly Ser His Thr Ile

530 535 540

Glu Phe Phe Glu Met Cys Ala Asn Leu Ile Lys Ile Leu Ala Gln

545 550 555

<210> SEQ ID NO: 23

<211> LENGTH: 5130

<212> TYPE: DNA

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic

<400> SEQENCE: 23

agcgccatgc gcagactcag ttcctggaga aagatggcga cagccgagaa gcagaaacac 60

gacgggcggg tgaagatcgg ccactacatt ctgggtgaca cgctgggggt cggcaccttc 120

ggcaaagtga aggttggcaa acatgaattg actgggcata aagtagctgt gaagatactc 180

aatcgacaga agattcggag ccttgatgtg gtaggaaaaa tccgcagaga aattcagaac 240

ctcaagcttt tcaggcatcc tcatataatt aaactgtacc aggtcatcag tacaccatct 300

gatattttca tggtgatgga atatgtctca ggaggagagc tatttgatta tatctgtaag 360

aatggaagga aatctgatgt acctggagta gtaaaaacag gctccacgaa ggagctggat 420

gaaaaagaaa gtcggcgtct gttccaacag atcctttctg gtgtggatta ttgtcacagg 480

catatggtgg tccatagaga tttgaaacct gaaaatgtcc tgcttgatgc acacatgaat 540

gcaaagatag ctgattttgg tctttcaaac atgatgtcag atggtgaatt tttaagaaca 600

agttgtggct cacccaacta tgctgcacca gaagtaattt caggaagatt gtatgcaggc 660

ccagaggtag atatatggag cagtggggtt attctctatg ctttattatg tggaaccctt 720

ccatttgatg atgaccatgt gccaactctt tttaagaaga tatgtgatgg gatcttctat 780

acccctcaat atttaaatcc ttctgtgatt agccttttga aacatatgct gcaggtggat 840

cccatgaaga gggccacaat caaagatatc agggaacatg aatggtttaa acaggacctt 900

ccaaaatatc tctttcctga ggatccatca tatagttcaa ccatgattga tgatgaagcc 960

ttaaaagaag tatgtgaaaa gtttgagtgc tcagaagagg aagttctcag ctgtctttac 1020

aacagaaatc accaggatcc tttggcagtt gcctaccatc tcataataga taacaggaga 1080

ataatgaatg aagccaaaga tttctatttg gcgacaagcc cacctgattc ttttcttgat 1140

gatcatcacc tgactcggcc ccatcctgaa agagtaccat tcttggttgc tgaaacacca 1200

agggcacgcc atacccttga tgaattaaat ccacagaaat ccaaacacca aggtgtaagg 1260

aaagcaaaat ggcatttagg aattagaagt caaagtcgac caaatgatat tatggcagaa 1320

gtatgtagag caatcaaaca attggattat gaatggaagg ttgtaaaccc atattatttg 1380

cgtgtacgaa ggaagaatcc tgtgacaagc acttactcca aaatgagtct acagttatac 1440

caagtggata gtagaactta tctactggat ttccgtagta ttgatgatga aattacagaa 1500

gccaaatcag ggactgctac tccacagaga tcgggatcag ttagcaacta tcgatcttgc 1560

caaaggagtg attcagatgc tgaggctcaa ggaaaatcct cagaagtttc tcttacctca 1620

tctgtgacct cacttgactc ttctcctgtt gacctaactc caagacctgg aagtcacaca 1680

atagaatttt ttgagatgtg tgcaaatcta attaaaattc ttgcacaata aacagaaaac 1740

tttgcttatt tcttttgcag caataagcat gcataataag tcacagccaa atgcttccat 1800

ttgtaatcaa gttatacata attataaccg agggctggcg ttttggaatg caatttgcac 1860

agggattgga acatgattta tagttaaaag cctaatatgc agaaatgaat taagatcatt 1920

ttgttgttca ttgtgcagta tgtatatagc ataatataca cagtgaatta taggtctcag 1980

gcttacttga tttttggcta ttttatattt agtgtacaca gggctttgaa atattaattt 2040

acataaaggc cttcatatat tattacgtgt tatatattac gtgttataaa tttattcaat 2100

aaatatttgc ctagaattcc caagaccttt ataggtgatt ttgttttctg ggctccttaa 2160

cttcataaat agctagtatc ttccagcagt agtaacagtc tggataactt cttccatatc 2220

cctccctctt tgtttttttg agacagtgtc actttgtcac ccaggctgga gtgcaatggt 2280

gtggtctcgg ctcactgcaa cctccacctc ccgggttcaa gtgattctcc cgcctcagct 2340

tcctgagtag ctggaactac aggcgtgtgc caccacaccc ggctaatttt tcgtattttt 2400

agtgtagacg gggtttcact atgttgccca ggctggtctc gaactcctga ccgcgtgatc 2460

caccacctca gcttcccaaa gtggtgggat tacaggcgtg agccaccgca cccggcctcc 2520

atatccccct tttaaaattc tgtagtgtat ggtaagtcat atcagatatc agacctaatt 2580

taaatttcat tttagcttta caagtccaaa aacacagaat ttatatattc agatactcta 2640

gcactaattt tagtcttaaa atattcccac gatattctgt acacaaaatg ttctttttgt 2700

tacaagagct gagttgcata tactgtagat aaatcatatt atttttgcca atttcacaaa 2760

ttcctctggc ccatcatgtc agtcattatt gagtatatgc acacattgct acttatttga 2820

ttatgtatct tttaaattga ttcagtgcat agaaaactat ctcttacaaa ctttaagtgc 2880

tctgatatga cttccccccc aaattttatt atgaacattt ttaaaaacag aaaaattgaa 2940

aaactgtttg gtaagcacat gtatatctac catttagatt cagcagttgt taatgttttg 3000

tcatttgttt tctctatacc tatatatgta tagatacagc tagttatgca tatatatgca 3060

tatatgtgtt tgtttgtgta tgtatatatg cttttttccc cctgaaccat ttggatgtta 3120

cagacatact tatcaccgtg aaaatacttc aagtatctcc tacagataat gacattctcc 3180

taaaaatccg taataccatt gtaaaagtaa taattcccca atatcatcta atcaagccat 3240

atttaaattt ctgaagttaa ctccaaattt ctttatagct gattatttca aactaggatc 3300

caattaaagt ttacatatga cacttggtta taactcttta gttggatata acattattat 3360

tattttgata aaatatggaa caaatcaatt ctattaataa gtggtcacat ttgttttggg 3420

cttaaattac tttttaaaga tactggattt tcctaagatt tctgatttac actgatattt 3480

ttttttgtca ttcttaattg catcacacaa tagatgtaaa tgaagatgta gtcacctcag 3540

ataaaattgg tatcgtgtat gataatattg tatcatttat atttgcctta tgttaacttt 3600

aagaaattga tttttttgta ttaatcattt tcccattgca acagagctat attttttcta 3660

ttttaagaat catattttag gattattttt ggcaaataca gtgagcactt atgtaaccag 3720

atgataatga actcaaatgt catgatagct tgcataaatg gtgactctag tagatttgac 3780

tcaagcactt ctagaatcat gcactgaatt caaaagaaaa atcttgctgc tttttgtcca 3840

gggcttgttc tattcaactt ctaatttgaa agctgtacaa agtaatagaa gttccattta 3900

aatatgagtt caaaactgta tttacttttt atgtggccct ctctttaggg gattctaatt 3960

ttacttaggg tctctaagtg cagcataatg ttcctgatgt taacagaaga ctgtattttt 4020

aaagttacaa atttgtatat ggaattaagt aatggcgcta tatacgctgt tgtggggagg 4080

ggggaagaaa aggaggaacc aattaaatag gaccttttaa aaattgttaa ttttgtaaac 4140

tttgcttctc ttataagtta ttgtgattca ttttagttac tgtgttttat tttgaaaata 4200

tttaaatatt gcacttctat aaatagtatg ataaatgcac agacaattgc agtaaattct 4260

tttttaagct aggatatttg aaatgacaac ctttggttaa gtgtgtcaag gttgcaacag 4320

aattttcaca atttttttgt tgtttgcaaa ttgttactaa tattgaagag gtaagggagg 4380

caatgcaaat gatttttaat ctttttttat tatcttttca gcagtttata ttttttgtga 4440

ctttatgcaa ccatattttt actttgtctt gacaactgaa agatgtataa ggttttttgc 4500

cagaaatgta ctgtatacat agttttaagt ataacagatt ttactgatat gtaaaaattt 4560

tgccattaaa ataaatgatt tctcactgag aggaactttt ctaccaggtt ggggcatatg 4620

ggagcttaat atatcatatc taatttaaaa taatttcact gaaataaact ccattgcttt 4680

tacctaattt ttttcttgag atgcttttgt agtttttcag agttttagat gattttatac 4740

aaaatcctct gcctagcact gctctttttg atgttgtagt gacaccattt acattgaatt 4800

aatgcttggt agcctggggc tagatgtgga actccatgga tctgtgttct gactggcacc 4860

tttggaatga aagaaaagtg tgtgctgtcc aaattttttc cccttaattc tttccctcat 4920

cttctcaccc ataatagaaa ttttatttcc attgtgagtt ctgacaagaa tgaaattcca 4980

catacaacat aactgtaaat tgttggtagg tagaagttaa tatttgtggt tcatgtatat 5040

tttgaccaga gtatatttaa gtatataatt tcagcttcct tgatttagaa atatgatata 5100

ataaagaaaa actccattta tcatctgtta 5130

<210> SEQ ID NO: 24

<211> LENGTH: 574

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic

<400> SEQENCE: 24

Met Arg Arg Leu Ser Ser Trp Arg Lys Met Ala Thr Ala Glu Lys Gln

1 5 10 15

Lys His Asp Gly Arg Val Lys Ile Gly His Tyr Ile Leu Gly Asp Thr

20 25 30

Leu Gly Val Gly Thr Phe Gly Lys Val Lys Val Gly Lys His Glu Leu

35 40 45

Thr Gly His Lys Val Ala Val Lys Ile Leu Asn Arg Gln Lys Ile Arg

50 55 60

Ser Leu Asp Val Val Gly Lys Ile Arg Arg Glu Ile Gln Asn Leu Lys

65 70 75 80

Leu Phe Arg His Pro His Ile Ile Lys Leu Tyr Gln Val Ile Ser Thr

85 90 95

Pro Ser Asp Ile Phe Met Val Met Glu Tyr Val Ser Gly Gly Glu Leu

100 105 110

Phe Asp Tyr Ile Cys Lys Asn Gly Arg Lys Ser Asp Val Pro Gly Val

115 120 125

Val Lys Thr Gly Ser Thr Lys Glu Leu Asp Glu Lys Glu Ser Arg Arg

130 135 140

Leu Phe Gln Gln Ile Leu Ser Gly Val Asp Tyr Cys His Arg His Met

145 150 155 160

Val Val His Arg Asp Leu Lys Pro Glu Asn Val Leu Leu Asp Ala His

165 170 175

Met Asn Ala Lys Ile Ala Asp Phe Gly Leu Ser Asn Met Met Ser Asp

180 185 190

Gly Glu Phe Leu Arg Thr Ser Cys Gly Ser Pro Asn Tyr Ala Ala Pro

195 200 205

Glu Val Ile Ser Gly Arg Leu Tyr Ala Gly Pro Glu Val Asp Ile Trp

210 215 220

Ser Ser Gly Val Ile Leu Tyr Ala Leu Leu Cys Gly Thr Leu Pro Phe

225 230 235 240

Asp Asp Asp His Val Pro Thr Leu Phe Lys Lys Ile Cys Asp Gly Ile

245 250 255

Phe Tyr Thr Pro Gln Tyr Leu Asn Pro Ser Val Ile Ser Leu Leu Lys

260 265 270

His Met Leu Gln Val Asp Pro Met Lys Arg Ala Thr Ile Lys Asp Ile

275 280 285

Arg Glu His Glu Trp Phe Lys Gln Asp Leu Pro Lys Tyr Leu Phe Pro

290 295 300

Glu Asp Pro Ser Tyr Ser Ser Thr Met Ile Asp Asp Glu Ala Leu Lys

305 310 315 320

Glu Val Cys Glu Lys Phe Glu Cys Ser Glu Glu Glu Val Leu Ser Cys

325 330 335

Leu Tyr Asn Arg Asn His Gln Asp Pro Leu Ala Val Ala Tyr His Leu

340 345 350

Ile Ile Asp Asn Arg Arg Ile Met Asn Glu Ala Lys Asp Phe Tyr Leu

355 360 365

Ala Thr Ser Pro Pro Asp Ser Phe Leu Asp Asp His His Leu Thr Arg

370 375 380

Pro His Pro Glu Arg Val Pro Phe Leu Val Ala Glu Thr Pro Arg Ala

385 390 395 400

Arg His Thr Leu Asp Glu Leu Asn Pro Gln Lys Ser Lys His Gln Gly

405 410 415

Val Arg Lys Ala Lys Trp His Leu Gly Ile Arg Ser Gln Ser Arg Pro

420 425 430

Asn Asp Ile Met Ala Glu Val Cys Arg Ala Ile Lys Gln Leu Asp Tyr

435 440 445

Glu Trp Lys Val Val Asn Pro Tyr Tyr Leu Arg Val Arg Arg Lys Asn

450 455 460

Pro Val Thr Ser Thr Tyr Ser Lys Met Ser Leu Gln Leu Tyr Gln Val

465 470 475 480

Asp Ser Arg Thr Tyr Leu Leu Asp Phe Arg Ser Ile Asp Asp Glu Ile

485 490 495

Thr Glu Ala Lys Ser Gly Thr Ala Thr Pro Gln Arg Ser Gly Ser Val

500 505 510

Ser Asn Tyr Arg Ser Cys Gln Arg Ser Asp Ser Asp Ala Glu Ala Gln

515 520 525

Gly Lys Ser Ser Glu Val Ser Leu Thr Ser Ser Val Thr Ser Leu Asp

530 535 540

Ser Ser Pro Val Asp Leu Thr Pro Arg Pro Gly Ser His Thr Ile Glu

545 550 555 560

Phe Phe Glu Met Cys Ala Asn Leu Ile Lys Ile Leu Ala Gln

565 570

<210> SEQ ID NO: 25

<211> LENGTH: 1501

<212> TYPE: DNA

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic

<400> SEQENCE: 25

ggagagagcc gccgagccga gccgagcccc agctccagca agagcgcggg cgggtggccc 60

aggcacgcag cggtgaggac cgcggccaca gctcggcgcc aaccaccgcg ggcctcccag 120

ccagccccgc ggcggggcag ccgcaggagc cctggctgtg gtcggggggc agtgggccat 180

gctgggggca gtggaaggcc ccaggtggaa gcaggcggag gacattagag acatctacga 240

cttccgagat gttctgggca cgggggcctt ctcggaggtg atcctggcag aagataagag 300

gacgcagaag ctggtggcca tcaaatgcat tgccaaggag gccctggagg gcaaggaagg 360

cagcatggag aatgagattg ctgtcctgca caagatcaag caccccaaca ttgtagccct 420

ggatgacatc tatgagagtg ggggccacct ctacctcatc atgcagctgg tgtcgggtgg 480

ggagctcttt gaccgtattg tggaaaaagg cttctacacg gagcgggacg ccagccgcct 540

catcttccag gtgctggatg ctgtgaaata cctgcatgac ctgggcattg tacaccggga 600

tctcaagcca gagaatctgc tgtactacag cctggatgaa gactccaaaa tcatgatctc 660

cgactttggc ctctccaaga tggaggaccc gggcagtgtg ctctccaccg cctgtggaac 720

tccgggatac gtggcccctg aagtcctggc ccagaagccc tacagcaagg ctgtggattg 780

ctggtccata ggtgtcatcg cctacatctt gctctgcggt taccctccct tctatgacga 840

gaatgatgcc aaactctttg aacagatttt gaaggccgag tacgagtttg actctcctta 900

ctgggacgac atctctgact ctgccaaaga tttcatccgg cacttgatgg agaaggaccc 960

agagaaaaga ttcacctgtg agcaggcctt gcagcaccca tggattgcag gagatacagc 1020

tctagataag aatatccacc agtcggtgag tgagcagatc aagaagaact ttgccaagag 1080

caagtggaag caagccttca atgccacggc tgtggtgcgg cacatgagga aactgcagct 1140

gggcaccagc caggaggggc aggggcagac ggcgagccat ggggagctgc tgacaccagt 1200

ggctgggggg ccggcagctg gctgttgctg tcgagactgc tgcgtggagc cgggcacaga 1260

actgtccccc acactgcccc accagctcta gggccctgga cctcgggtca tgatcctctg 1320

cgtgggaggg cttgggggca gcctgctccc cttccctccc tgaaccggga gtttctctgc 1380

cctgtcccct cctcacctgc ttccctacca ctcctcactg cattttccat acaaatgttt 1440

ctattttatt gttccttctt gtaataaagg gaagataaaa ccaaaaaaaa aaaaaaaaaa 1500

a 1501

<210> SEQ ID NO: 26

<211> LENGTH: 370

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic

<400> SEQENCE: 26

Met Leu Gly Ala Val Glu Gly Pro Arg Trp Lys Gln Ala Glu Asp Ile

1 5 10 15

Arg Asp Ile Tyr Asp Phe Arg Asp Val Leu Gly Thr Gly Ala Phe Ser

20 25 30

Glu Val Ile Leu Ala Glu Asp Lys Arg Thr Gln Lys Leu Val Ala Ile

35 40 45

Lys Cys Ile Ala Lys Glu Ala Leu Glu Gly Lys Glu Gly Ser Met Glu

50 55 60

Asn Glu Ile Ala Val Leu His Lys Ile Lys His Pro Asn Ile Val Ala

65 70 75 80

Leu Asp Asp Ile Tyr Glu Ser Gly Gly His Leu Tyr Leu Ile Met Gln

85 90 95

Leu Val Ser Gly Gly Glu Leu Phe Asp Arg Ile Val Glu Lys Gly Phe

100 105 110

Tyr Thr Glu Arg Asp Ala Ser Arg Leu Ile Phe Gln Val Leu Asp Ala

115 120 125

Val Lys Tyr Leu His Asp Leu Gly Ile Val His Arg Asp Leu Lys Pro

130 135 140

Glu Asn Leu Leu Tyr Tyr Ser Leu Asp Glu Asp Ser Lys Ile Met Ile

145 150 155 160

Ser Asp Phe Gly Leu Ser Lys Met Glu Asp Pro Gly Ser Val Leu Ser

165 170 175

Thr Ala Cys Gly Thr Pro Gly Tyr Val Ala Pro Glu Val Leu Ala Gln

180 185 190

Lys Pro Tyr Ser Lys Ala Val Asp Cys Trp Ser Ile Gly Val Ile Ala

195 200 205

Tyr Ile Leu Leu Cys Gly Tyr Pro Pro Phe Tyr Asp Glu Asn Asp Ala

210 215 220

Lys Leu Phe Glu Gln Ile Leu Lys Ala Glu Tyr Glu Phe Asp Ser Pro

225 230 235 240

Tyr Trp Asp Asp Ile Ser Asp Ser Ala Lys Asp Phe Ile Arg His Leu

245 250 255

Met Glu Lys Asp Pro Glu Lys Arg Phe Thr Cys Glu Gln Ala Leu Gln

260 265 270

His Pro Trp Ile Ala Gly Asp Thr Ala Leu Asp Lys Asn Ile His Gln

275 280 285

Ser Val Ser Glu Gln Ile Lys Lys Asn Phe Ala Lys Ser Lys Trp Lys

290 295 300

Gln Ala Phe Asn Ala Thr Ala Val Val Arg His Met Arg Lys Leu Gln

305 310 315 320

Leu Gly Thr Ser Gln Glu Gly Gln Gly Gln Thr Ala Ser His Gly Glu

325 330 335

Leu Leu Thr Pro Val Ala Gly Gly Pro Ala Ala Gly Cys Cys Cys Arg

340 345 350

Asp Cys Cys Val Glu Pro Gly Thr Glu Leu Ser Pro Thr Leu Pro His

355 360 365

Gln Leu

370

<210> SEQ ID NO: 27

<211> LENGTH: 1888

<212> TYPE: DNA

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic

<400> SEQENCE: 27

gacttggatt gacatagaga gctgcaggag ggtgacatga tctcaataaa aggaatgctc 60

tggctgctgg gtagagaaga aagcgagggt gagggattaa tggtggagcc agagggagcc 120

cagtgagtgc cgggagccca gggtggcaga gctgtggtgc agggttgcag ggtcctggag 180

ctaggcatgg aggctgcttt cgggcaagtg gccgggtcag cctgtcctcg gagaggcggt 240

gaaggcagag actggaaggc agagagcctt gccgacctgt ggccgaagag ctctccggga 300

gacagccacc ggtggtgcaa aggccctggg gccggcccag ccgggccgca gctccgggag 360

gcggcgcgag cgagcagtgg gctgggcggt ggcggccggc acccgagccg gatcccggcg 420

attgccttac aagacatgct gctgctgaag aaacacacgg aggacatcag cagcgtctac 480

gagatccgcg agaggctcgg ctcgggtgcc ttctccgagg tggtgctggc ccaggagcgg 540

ggctccgcac acctcgtggc cctcaagtgc atccccaaga aggccctccg gggcaaggag 600

gccctggtgg agaacgagat cgcagtgctc cgtaggatca gtcaccccaa catcgtcgct 660

ctggaggatg tccacgagag cccttcccac ctctacctgg ccatggaact ggtgacgggt 720

ggcgagctgt ttgaccgcat catggagcgc ggctcctaca cagagaagga tgccagccat 780

ctggtgggtc aggtccttgg cgccgtctcc tacctgcaca gcctggggat cgtgcaccgg 840

gacctcaagc ccgaaaacct cctgtatgcc acgccctttg aggactcgaa gatcatggtc 900

tctgactttg gactctccaa aatccaggct gggaacatgc taggcaccgc ctgtgggacc 960

cctggatatg tggccccaga gctcttggag cagaaaccct acgggaaggc cgtagatgtg 1020

tgggccctgg gcgtcatctc ctacatcctg ctgtgtgggt accccccctt ctacgacgag 1080

agcgaccctg agctcttcag ccagatcctg agggccagct atgagtttga ctctcctttc 1140

tgggatgaca tctcagaatc agccaaagac ttcatccggc accttctgga gcgagacccc 1200

cagaagaggt tcacctgcca acaggccttg cggcaccttt ggatctctgg ggacacagcc 1260

ttcgacaggg acatcttagg ctctgtcagt gagcagatcc ggaagaactt tgctcggaca 1320

cactggaagc gagccttcaa tgccacctcg ttcctgcgcc acatccggaa gctggggcag 1380

atcccagagg gcgagggggc ctctgagcag ggcatggccc gccacagcca ctcaggcctc 1440

cgtgctggcc agccccccaa gtggtgatgc ccaggcagat gccgaggcca agtggactga 1500

cccccagatt tccttccctt ggatgctttc ggtcccctcc cccaacccct ccccctgggg 1560

ctggcctctg ctggattttg agatttgagg gtgtggcgca tggcgctggg gttggaatgg 1620

ggcaccccca agtctgtccc caggctctgc cctgcctggg ggcagtggct cccctcccct 1680

gttgcctctc ccgcccctgc cccccccgcc ccgccaaaag ccgagggggt gctggcaggc 1740

gggcctcagg ggctgtcttt cctgcacggc tgttgtgtgc ttcgctgagt gtgggtggtc 1800

ctgcttgtgt catggtcatg gccttccagc cccctccagt tttccccaaa ccaataaaga 1860

aagatacagc aaaaaaaaaa aaaaaaaa 1888

<210> SEQ ID NO: 28

<211> LENGTH: 426

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic

<400> SEQENCE: 28

Met Glu Ala Ala Phe Gly Gln Val Ala Gly Ser Ala Cys Pro Arg Arg

1 5 10 15

Gly Gly Glu Gly Arg Asp Trp Lys Ala Glu Ser Leu Ala Asp Leu Trp

20 25 30

Pro Lys Ser Ser Pro Gly Asp Ser His Arg Trp Cys Lys Gly Pro Gly

35 40 45

Ala Gly Pro Ala Gly Pro Gln Leu Arg Glu Ala Ala Arg Ala Ser Ser

50 55 60

Gly Leu Gly Gly Gly Gly Arg His Pro Ser Arg Ile Pro Ala Ile Ala

65 70 75 80

Leu Gln Asp Met Leu Leu Leu Lys Lys His Thr Glu Asp Ile Ser Ser

85 90 95

Val Tyr Glu Ile Arg Glu Arg Leu Gly Ser Gly Ala Phe Ser Glu Val

100 105 110

Val Leu Ala Gln Glu Arg Gly Ser Ala His Leu Val Ala Leu Lys Cys

115 120 125

Ile Pro Lys Lys Ala Leu Arg Gly Lys Glu Ala Leu Val Glu Asn Glu

130 135 140

Ile Ala Val Leu Arg Arg Ile Ser His Pro Asn Ile Val Ala Leu Glu

145 150 155 160

Asp Val His Glu Ser Pro Ser His Leu Tyr Leu Ala Met Glu Leu Val

165 170 175

Thr Gly Gly Glu Leu Phe Asp Arg Ile Met Glu Arg Gly Ser Tyr Thr

180 185 190

Glu Lys Asp Ala Ser His Leu Val Gly Gln Val Leu Gly Ala Val Ser

195 200 205

Tyr Leu His Ser Leu Gly Ile Val His Arg Asp Leu Lys Pro Glu Asn

210 215 220

Leu Leu Tyr Ala Thr Pro Phe Glu Asp Ser Lys Ile Met Val Ser Asp

225 230 235 240

Phe Gly Leu Ser Lys Ile Gln Ala Gly Asn Met Leu Gly Thr Ala Cys

245 250 255

Gly Thr Pro Gly Tyr Val Ala Pro Glu Leu Leu Glu Gln Lys Pro Tyr

260 265 270

Gly Lys Ala Val Asp Val Trp Ala Leu Gly Val Ile Ser Tyr Ile Leu

275 280 285

Leu Cys Gly Tyr Pro Pro Phe Tyr Asp Glu Ser Asp Pro Glu Leu Phe

290 295 300

Ser Gln Ile Leu Arg Ala Ser Tyr Glu Phe Asp Ser Pro Phe Trp Asp

305 310 315 320

Asp Ile Ser Glu Ser Ala Lys Asp Phe Ile Arg His Leu Leu Glu Arg

325 330 335

Asp Pro Gln Lys Arg Phe Thr Cys Gln Gln Ala Leu Arg His Leu Trp

340 345 350

Ile Ser Gly Asp Thr Ala Phe Asp Arg Asp Ile Leu Gly Ser Val Ser

355 360 365

Glu Gln Ile Arg Lys Asn Phe Ala Arg Thr His Trp Lys Arg Ala Phe

370 375 380

Asn Ala Thr Ser Phe Leu Arg His Ile Arg Lys Leu Gly Gln Ile Pro

385 390 395 400

Glu Gly Glu Gly Ala Ser Glu Gln Gly Met Ala Arg His Ser His Ser

405 410 415

Gly Leu Arg Ala Gly Gln Pro Pro Lys Trp

420 425

<210> SEQ ID NO: 29

<211> LENGTH: 1727

<212> TYPE: DNA

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic

<400> SEQENCE: 29

agccggcgcg cggcggcggc aggaagtctg tgcccgagaa cagcagaaat aagagccagg 60

gagggaccgc ggccgcggcg gcggcggcga gagcgaaaga ggaaactgca gaggaggaag 120

ctgcgccgca gcccgagccg cccggcatcc ccgccgcctc tgcgcccgcg ccgcgccccc 180

ggcgccccct ccccagcgcg cccccggccg ctcctccgcg ccgcgctcgt cggccatggc 240

ccgggagaac ggcgagagca gctcctcctg gaaaaagcaa gctgaagaca tcaagaagat 300

cttcgagttc aaagagaccc tcggaaccgg ggccttttcc gaagtggttt tagctgaaga 360

gaaggcaact ggcaagctct ttgctgtgaa gtgtatccct aagaaggcgc tgaagggcaa 420

ggaaagcagc atagagaatg agatagccgt cctgagaaag attaagcatg aaaatattgt 480

tgccctggaa gacatttatg aaagcccaaa tcacctgtac ttggtcatgc agctggtgtc 540

cggtggagag ctgtttgacc ggatagtgga gaaggggttt tatacagaga aggatgccag 600

cactctgatc cgccaagtct tggacgccgt gtactatctc cacagaatgg gcatcgtcca 660

cagagacctc aagcccgaaa atctcttgta ctacagtcaa gatgaggagt ccaaaataat 720

gatcagtgac tttggattgt caaaaatgga gggcaaagga gatgtgatgt ccactgcctg 780

tggaactcca ggctatgtcg ctcctgaagt cctcgcccag aaaccttaca gcaaagccgt 840

tgactgctgg tccatcggag tgattgccta catcttgctc tgcggctacc ctccttttta 900

tgatgaaaat gactccaagc tctttgagca gatcctcaag gcggaatatg agtttgactc 960

tccctactgg gatgacatct ccgactctgc aaaagacttc attcggaacc tgatggagaa 1020

ggacccgaat aaaagataca cgtgtgagca ggcagctcgg cacccatgga tcgctggtga 1080

cacagccctc aacaaaaaca tccacgagtc cgtcagcgcc cagatccgga aaaactttgc 1140

caagagcaaa tggagacaag catttaatgc cacggccgtc gtcagacata tgagaaaact 1200

acacctcggc agcagcctgg acagttcaaa tgcaagtgtt tcgagcagcc tcagtttggc 1260

cagccaaaaa gactgtgcgt atgtagcaaa accagaatcc ctcagctgac actgaagacg 1320

agcctggggt ggagaggagg gagccggcat ctgccgagca cctcctgttt gccaggcgct 1380

ttctatactt aatcccatgt catgcgaccc taggactttt tttaacatgt aatcactggg 1440

ctgggtgcag tggctcacgc ctgtaatccc aacactttgg gaggctgagg caggaggact 1500

gtttgagttc aggagtttta agaccagcct gaccaacatg gtgaaacccc atctctacta 1560

aaatataaaa attagccggg tgtggtggcg agcacctgta atgtcagcta cttgggaggc 1620

tgaggcagga gaatcacttg aacccaggaa gcggaggttg caatgagctg agatcacacc 1680

actgcactcc agcctgggtg acagattgag actccctctc aaaaaaa 1727

<210> SEQ ID NO: 30

<211> LENGTH: 357

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic

<400> SEQENCE: 30

Met Ala Arg Glu Asn Gly Glu Ser Ser Ser Ser Trp Lys Lys Gln Ala

1 5 10 15

Glu Asp Ile Lys Lys Ile Phe Glu Phe Lys Glu Thr Leu Gly Thr Gly

20 25 30

Ala Phe Ser Glu Val Val Leu Ala Glu Glu Lys Ala Thr Gly Lys Leu

35 40 45

Phe Ala Val Lys Cys Ile Pro Lys Lys Ala Leu Lys Gly Lys Glu Ser

50 55 60

Ser Ile Glu Asn Glu Ile Ala Val Leu Arg Lys Ile Lys His Glu Asn

65 70 75 80

Ile Val Ala Leu Glu Asp Ile Tyr Glu Ser Pro Asn His Leu Tyr Leu

85 90 95

Val Met Gln Leu Val Ser Gly Gly Glu Leu Phe Asp Arg Ile Val Glu

100 105 110

Lys Gly Phe Tyr Thr Glu Lys Asp Ala Ser Thr Leu Ile Arg Gln Val

115 120 125

Leu Asp Ala Val Tyr Tyr Leu His Arg Met Gly Ile Val His Arg Asp

130 135 140

Leu Lys Pro Glu Asn Leu Leu Tyr Tyr Ser Gln Asp Glu Glu Ser Lys

145 150 155 160

Ile Met Ile Ser Asp Phe Gly Leu Ser Lys Met Glu Gly Lys Gly Asp

165 170 175

Val Met Ser Thr Ala Cys Gly Thr Pro Gly Tyr Val Ala Pro Glu Val

180 185 190

Leu Ala Gln Lys Pro Tyr Ser Lys Ala Val Asp Cys Trp Ser Ile Gly

195 200 205

Val Ile Ala Tyr Ile Leu Leu Cys Gly Tyr Pro Pro Phe Tyr Asp Glu

210 215 220

Asn Asp Ser Lys Leu Phe Glu Gln Ile Leu Lys Ala Glu Tyr Glu Phe

225 230 235 240

Asp Ser Pro Tyr Trp Asp Asp Ile Ser Asp Ser Ala Lys Asp Phe Ile

245 250 255

Arg Asn Leu Met Glu Lys Asp Pro Asn Lys Arg Tyr Thr Cys Glu Gln

260 265 270

Ala Ala Arg His Pro Trp Ile Ala Gly Asp Thr Ala Leu Asn Lys Asn

275 280 285

Ile His Glu Ser Val Ser Ala Gln Ile Arg Lys Asn Phe Ala Lys Ser

290 295 300

Lys Trp Arg Gln Ala Phe Asn Ala Thr Ala Val Val Arg His Met Arg

305 310 315 320

Lys Leu His Leu Gly Ser Ser Leu Asp Ser Ser Asn Ala Ser Val Ser

325 330 335

Ser Ser Leu Ser Leu Ala Ser Gln Lys Asp Cys Ala Tyr Val Ala Lys

340 345 350

Pro Glu Ser Leu Ser

355

<210> SEQ ID NO: 31

<211> LENGTH: 2507

<212> TYPE: DNA

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic

<400> SEQENCE: 31

tggagcagct aatcctcaca gacctgtagg agctggagtg ggagctcaag caggattctt 60

cccgagtccc tggcatcctc agaagcttca actctggagg caatgggtcg aaaggaagaa 120

gatgactgca gttcctggaa gaaacagacc accaacatcc ggaaaacctt catttttatg 180

gaagtgctgg gatcaggagc tttctcagaa gttttcctgg tgaagcaaag actgactggg 240

aagctctttg ctctgaagtg catcaagaag tcacctgcct tccgggacag cagcctggag 300

aatgagattg ctgtgttgaa aaagatcaag catgaaaaca ttgtgaccct ggaggacatc 360

tatgagagca ccacccacta ctacctggtc atgcagcttg tttctggtgg ggagctcttt 420

gaccggatcc tggagcgggg tgtctacaca gagaaggatg ccagtctggt gatccagcag 480

gtcttgtcgg cagtgaaata cctacatgag aatggcatcg tccacagaga cttaaagccc 540

gaaaacctgc tttaccttac ccctgaagag aactctaaga tcatgatcac tgactttggt 600

ctgtccaaga tggaacagaa tggcatcatg tccactgcct gtgggacccc aggctacgtg 660

gctccagaag tgctggccca gaaaccctac agcaaggctg tggattgctg gtccatcggc 720

gtcatcacct acatattgct ctgtggatac cccccattct atgaagaaac ggagtctaag 780

cttttcgaga agatcaagga gggctactat gagtttgagt ctccattctg ggatgacatt 840

tctgagtcag ccaaggactt tatttgccac ttgcttgaga aggatccgaa cgagcggtac 900

acctgtgaga aggccttgag tcatccctgg attgacggaa acacagccct ccaccgggac 960

atctacccat cagtcagcct ccagatccag aagaactttg ctaagagcaa gtggaggcaa 1020

gccttcaacg cagcagctgt ggtgcaccac atgaggaagc tacacatgaa cctgcacagc 1080

ccgggcgtcc gcccagaggt ggagaacagg ccgcctgaaa ctcaagcctc agaaacctct 1140

agacccagct cccctgagat caccatcacc gaggcacctg tcctggacca cagtgtagca 1200

ctccctgccc tgacccaatt accctgccag catggccgcc ggcccactgc ccctggtggc 1260

aggtccctca actgcctggt caatggctcc ctccacatca gcagcagcct ggtgcccatg 1320

catcaggggt ccctggccgc cgggccctgt ggctgctgct ccagctgcct gaacattggg 1380

agcaaaggaa agtcctccta ctgctctgag cccacactcc tcaaaaaggc caacaaaaaa 1440

cagaacttca agtcggaggt catggtacca gttaaagcca gtggcagctc ccactgccgg 1500

gcagggcaga ctggagtctg tctcattatg tgattcctgg agcctgtgcc tatgtcactg 1560

caattttcag gagacatatt caactcctct gctcttccaa acctggtgtc tatccggcag 1620

agggaggaag gcagagcaag tggagcaggg cttagcagga gcagtttctg gccagaagca 1680

ccagcctgct gccagcgggg cagcccctca taggaggccc aggagggagc cccaaggcgt 1740

agaagccttg ttgaagctgt gagcaggaga agcggtgccc accagcttcc aggtctccct 1800

gacctgcctg ctctatgccc cacaccctac gtgccgtggc tctgtgcagt gtacgtagat 1860

agctctcgcc tgggtctgtg ctgtttgtcg tgaaaagctt aatgggctgg ccaggctgtg 1920

tcaccttctc caagcaaagc catatggagc atctacccag actcccactc tgcacacact 1980

cactcccacc tctcaagcct ccaacctctt ggccagattg ggctcattaa tgtcgttgcc 2040

tgcccatctg catgaatgac aggcagctcc ccatggtggt ctgcctgtga gctcttcaag 2100

ttctaatcct taactccagg attagctccc aagtgcgctg agacccagcc agcacacttc 2160

tggcccttct ccctgcctca atctaaaagc agtgccacac cctccaaagt ggaatagaaa 2220

gaagttcatg agtaagggct gcaaggaatt cttatcctgg ccacatgtcc tccgtgcaca 2280

cacccaatgg agttaacctt ggaagttgac tattttaatg tctgccagga gttctaatcc 2340

tgcctctgtt cccttttctc tccttgaaag tccagcacac cattcttgtc cttccccagt 2400

ttcctcgccc tccacccctc cagcttcatg ctcagtgttg tgcttaataa aatggacata 2460

tttttctcta aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaa 2507

<210> SEQ ID NO: 32

<211> LENGTH: 476

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic

<400> SEQENCE: 32

Met Gly Arg Lys Glu Glu Asp Asp Cys Ser Ser Trp Lys Lys Gln Thr

1 5 10 15

Thr Asn Ile Arg Lys Thr Phe Ile Phe Met Glu Val Leu Gly Ser Gly

20 25 30

Ala Phe Ser Glu Val Phe Leu Val Lys Gln Arg Leu Thr Gly Lys Leu

35 40 45

Phe Ala Leu Lys Cys Ile Lys Lys Ser Pro Ala Phe Arg Asp Ser Ser

50 55 60

Leu Glu Asn Glu Ile Ala Val Leu Lys Lys Ile Lys His Glu Asn Ile

65 70 75 80

Val Thr Leu Glu Asp Ile Tyr Glu Ser Thr Thr His Tyr Tyr Leu Val

85 90 95

Met Gln Leu Val Ser Gly Gly Glu Leu Phe Asp Arg Ile Leu Glu Arg

100 105 110

Gly Val Tyr Thr Glu Lys Asp Ala Ser Leu Val Ile Gln Gln Val Leu

115 120 125

Ser Ala Val Lys Tyr Leu His Glu Asn Gly Ile Val His Arg Asp Leu

130 135 140

Lys Pro Glu Asn Leu Leu Tyr Leu Thr Pro Glu Glu Asn Ser Lys Ile

145 150 155 160

Met Ile Thr Asp Phe Gly Leu Ser Lys Met Glu Gln Asn Gly Ile Met

165 170 175

Ser Thr Ala Cys Gly Thr Pro Gly Tyr Val Ala Pro Glu Val Leu Ala

180 185 190

Gln Lys Pro Tyr Ser Lys Ala Val Asp Cys Trp Ser Ile Gly Val Ile

195 200 205

Thr Tyr Ile Leu Leu Cys Gly Tyr Pro Pro Phe Tyr Glu Glu Thr Glu

210 215 220

Ser Lys Leu Phe Glu Lys Ile Lys Glu Gly Tyr Tyr Glu Phe Glu Ser

225 230 235 240

Pro Phe Trp Asp Asp Ile Ser Glu Ser Ala Lys Asp Phe Ile Cys His

245 250 255

Leu Leu Glu Lys Asp Pro Asn Glu Arg Tyr Thr Cys Glu Lys Ala Leu

260 265 270

Ser His Pro Trp Ile Asp Gly Asn Thr Ala Leu His Arg Asp Ile Tyr

275 280 285

Pro Ser Val Ser Leu Gln Ile Gln Lys Asn Phe Ala Lys Ser Lys Trp

290 295 300

Arg Gln Ala Phe Asn Ala Ala Ala Val Val His His Met Arg Lys Leu

305 310 315 320

His Met Asn Leu His Ser Pro Gly Val Arg Pro Glu Val Glu Asn Arg

325 330 335

Pro Pro Glu Thr Gln Ala Ser Glu Thr Ser Arg Pro Ser Ser Pro Glu

340 345 350

Ile Thr Ile Thr Glu Ala Pro Val Leu Asp His Ser Val Ala Leu Pro

355 360 365

Ala Leu Thr Gln Leu Pro Cys Gln His Gly Arg Arg Pro Thr Ala Pro

370 375 380

Gly Gly Arg Ser Leu Asn Cys Leu Val Asn Gly Ser Leu His Ile Ser

385 390 395 400

Ser Ser Leu Val Pro Met His Gln Gly Ser Leu Ala Ala Gly Pro Cys

405 410 415

Gly Cys Cys Ser Ser Cys Leu Asn Ile Gly Ser Lys Gly Lys Ser Ser

420 425 430

Tyr Cys Ser Glu Pro Thr Leu Leu Lys Lys Ala Asn Lys Lys Gln Asn

435 440 445

Phe Lys Ser Glu Val Met Val Pro Val Lys Ala Ser Gly Ser Ser His

450 455 460

Cys Arg Ala Gly Gln Thr Gly Val Cys Leu Ile Met

465 470 475

<210> SEQ ID NO: 33

<211> LENGTH: 4918

<212> TYPE: DNA

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic

<400> SEQENCE: 33

ggttgccatg gggacctgga tgctgacgaa ggctcgcgag gctgtgagca gccacagtgc 60

cctgctcaga agccccgggc tcgtcagtca aaccggttct ctgtttgcac tcggcagcac 120

gggcaggcaa gtggtcccta ggttcgggag cagagcagca gcgcctcagt cctggtcccc 180

cagtcccaag cctcacctgc ctgcccagcg ccaggatggc caccatcacc tgcacccgct 240

tcacggaaga gtaccagctc ttcgaggaat tgggcaaggg agccttctcg gtggtgcgaa 300

ggtgtgtgaa ggtgctggct ggccaggagt atgctgccaa gatcatcaac acaaagaagc 360

tgtcagccag agaccatcag aagctggagc gtgaagcccg catctgccgc ctgctgaagc 420

accccaacat cgtccgacta catgacagca tctcagagga gggacaccac tacctgatct 480

tcgacctggt cactggtggg gaactgtttg aagatatcgt ggcccgggag tattacagtg 540

aggcggatgc cagtcactgt atccagcaga tcctggaggc tgtgctgcac tgccaccaga 600

tgggggtggt gcaccgggac ctgaagcctg agaatctgtt gctggcctcc aagctcaagg 660

gtgccgcagt gaagctggca gactttggcc tggccataga ggtggagggg gagcagcagg 720

catggtttgg gtttgcaggg actcctggat atctctcccc agaagtgctg cggaaggacc 780

cgtacgggaa gcctgtggac ctgtgggctt gtggggtcat cctgtacatc ctgctggttg 840

ggtacccccc gttctgggat gaggaccagc accgcctgta ccagcagatc aaagccggcg 900

cctatgattt cccatcgccg gaatgggaca ctgtcacccc ggaagccaag gatctgatca 960

ataagatgct gaccattaac ccatccaaac gcatcacagc tgccgaagcc cttaagcacc 1020

cctggatctc gcaccgctcc accgtggcat cctgcatgca cagacaggag accgtggact 1080

gcctgaagaa gttcaatgcc aggaggaaac tgaagggagc cattctcacc acgatgctgg 1140

ccaccaggaa cttctccgga gggaagagtg ggggaaacaa gaagagcgat ggtgtgaaga 1200

aaagaaagtc cagttccagc gttcagttaa tggaatcctc agagagcacc aacaccacca 1260

tcgaggatga agacaccaaa gtgcggaaac aggaaattat aaaagtgaca gagcagctga 1320

ttgaagccat aagcaatgga gattttgagt cctacacgaa gatgtgcgac cctggcatga 1380

cagccttcga acctgaggcc ctggggaacc tggttgaggg cctggacttc catcgattct 1440

attttgaaaa cctgtggtcc cggaacagca agcccgtgca caccaccatc ctgaatcccc 1500

acatccacct gatgggcgac gagtcagcct gcatcgccta catccgcatc acgcagtacc 1560

tggacgctgg cggcatccca cgcaccgccc agtcggagga gacccgtgtc tggcaccgcc 1620

gggatggcaa atggcagatc gtccacttcc acagatctgg ggcgccctcc gtcctgcccc 1680

actgagggac caggctgggg tcgctgcgtt gctgtgccgc agagatccac tctgtccgtg 1740

gagtggagct gctggttctc ccaggtggat tttgctggaa ttctcccatg tcatcacccc 1800

accaccgtca cttctgtacc tgcatcaaga aaacctgctt gttcacaaaa gtcatcgcaa 1860

cttcagagcg aacggccaca tctccccacc tctcaccccc accctctccc ctgccaggct 1920

ggggcttcct caggcatggg tgtccacagc actggccccc tctccccagc ctcagctgct 1980

gtccgcctga tctgtcttgg gctgtaggct agaatgcccg ggctggtgcc caccaggggc 2040

tggggagaag gaggggtggc atgatgagga aggcagcatc cgtccgtccc tctcccagac 2100

ctctcctctt ccagtgtccc cggggaaggg cagatgacac tcccttcccc ctaagccaac 2160

cgcactgaag gagtggggag aagagcatac gccaggagcc tcctgcctca aagtgctccc 2220

ctaagtcttc ttcctcctgt gctgacctca gggtggtctg acccttccct cggtgtgggg 2280

gatgtggccc tctcaggtgc ccctacttgc tttctgcttc cttctggtga agtccacctc 2340

caacattaac ctgcccaccc cacccccgtc atccctggag aattccagct ttgtcgtatc 2400

tcagagaggg aatctaattg tttttggggg gcaaaagaaa gcaacgttta ggtatcactt 2460

ctacttggac cgcatgcctt tttatagcca aatttctgtg tatttcgtaa atggatttcg 2520

cgttaatgga tatttatgta ataactagac ttctcagatt attgtgagaa gggtcaggtt 2580

ggaaggggtg taggaagagg ggtgaggggt agtttttttc tgttctagtt tttttttttt 2640

tttttgtcat ctctgaggtg gaccttgtca cctgtggtta ttggggccaa ggtggactca 2700

gctccgggga gaagggcctc tctgccattt cggtcccaag gtgagctgac acaggcgttc 2760

cttttgggac tgtggaagca tcagatgcca gcactgactc aggaacagca agtcagggca 2820

gagaggagga gggaggctgt caggatggaa atacctggac ttttctttgc ttccctcgca 2880

aactggggtc ttctctaccg aacttcccag gatttcatct caccatatct gtgtgccgcc 2940

cccagcaccc cccacccacc tctggggggc ccgtgagcgt gtgtcttcat tgcctctctc 3000

cccttggcgt ctgatgacca cagcaaagca ctgggaattt ctactcttca tgcctcatcc 3060

tgcagcctcg ggttcgcatt ctctctttct tttcctcttt ccctctttcc ctgggattga 3120

ctctgagtgg aataccttgg cacatccact aggatctact gtctgcactg ttttctttgc 3180

atgactttat acgcagtaag tatgttgaaa acaaacaaaa agaagaaaac actcaacaaa 3240

accaatctac atgttttgga ctaaaaaaaa aaatagaggt tgtattctca gtgtccgact 3300

cggaattatg ttgctgcctc tctgtgcttt tggcctctgt gtggccgtgt tttgccagca 3360

tgagatactg tcccctctgg aggattttag gggaggaaga gccacgtccc cagggattgg 3420

aggaggctcc ggtaccctcg accctcctgg gtgttggttg gagcagaact ggtgaggatg 3480

tttgatccga gattttctga gctctcccca atcaccagct gtctgctggg ttcttttctc 3540

aagtcctgct gcccaggccc aggtgagaca ggcaacgcca ggtctgcagg ccaggagaga 3600

tgctgcccag gcctcctggt ttccaagctg gtccatcact ggcctctgtc cttggcagag 3660

accttgctgc ccaggcccag gggcaggctc ttggcctgcc ccaggcccag agggcttccc 3720

agtaaggccc agtgatccca ttatcccagg ggcaaaacca cctgtcccct tttgagctgc 3780

cagttcccta cagccatccc cagtcaaggg tgagggtgtg gccttcacca ggggctgctg 3840

taattaccga gcaaggtctg agctcttctt cagcctcagt tccctcattg gttaaaaggg 3900

ttctttgttc ccatccagcc gatgaaggag caaacgtctg gctatgtgaa gcctaattta 3960

cctgcaggaa ctggcaggga tagtcactgg ctggactcct gtttacttct agacctggtc 4020

aggctccatc ccctccccca cctgcccctg attcccctcg tcggtgcctg tcaactgctt 4080

ttcagcagtg gactgcaggg gaaagagcag tgatttgggg tgagtaggct tcaattccca 4140

gctctgacca gacttgctgt gtgaccttgg gcaagttcct ttccctcttt ggagcttggt 4200

ttccctgcca gaggaaactg agctggagga gcctgaggtc ctgcctttca ttggctgaca 4260

cacctcctgt ccactgtgtc actctccaag tgccagagaa gtggaggcag atcgctaccc 4320

caggctgaga tggcccccac tgtgaaggcc acgcctgtgg gtgggcagcc acctggtgcc 4380

accacagggc accagggatg atcctgatgt ggcaggcagg ggagactcac agaaaaatct 4440

gcccagagcc taccctcacc agacaaactc tgtgctcctc caaaacatcc tttagatgca 4500

aaataataat aataataata ataaataaat aaataaaaat ccaaacccaa gtcaaaacct 4560

tggctccagc atgaaaacac gtttacagga aagtgttctc ctgggtttgt gcccaccatg 4620

gtgcgaatcc tgacccaagg cctcctgtct cccttcaaag ggagaccctt ttgggggatg 4680

agtttgccag actccccgtg ctggtttctt tgttactatt tgtttggggt tttgttttag 4740

ttcttttttt ttttcttttc ttttttaaaa atatgtggct gtgaacttga atgaacactg 4800

ctcaaacttt ctgctattgg ggggggcggg tgggatggga agaaggggcg tttgttttat 4860

tcttggtgtt ttcagtgcaa taaatagcta caaacttctg tgcaaaaaaa aaaaaaaa 4918

<210> SEQ ID NO: 34

<211> LENGTH: 489

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic

<400> SEQENCE: 34

Met Ala Thr Ile Thr Cys Thr Arg Phe Thr Glu Glu Tyr Gln Leu Phe

1 5 10 15

Glu Glu Leu Gly Lys Gly Ala Phe Ser Val Val Arg Arg Cys Val Lys

20 25 30

Val Leu Ala Gly Gln Glu Tyr Ala Ala Lys Ile Ile Asn Thr Lys Lys

35 40 45

Leu Ser Ala Arg Asp His Gln Lys Leu Glu Arg Glu Ala Arg Ile Cys

50 55 60

Arg Leu Leu Lys His Pro Asn Ile Val Arg Leu His Asp Ser Ile Ser

65 70 75 80

Glu Glu Gly His His Tyr Leu Ile Phe Asp Leu Val Thr Gly Gly Glu

85 90 95

Leu Phe Glu Asp Ile Val Ala Arg Glu Tyr Tyr Ser Glu Ala Asp Ala

100 105 110

Ser His Cys Ile Gln Gln Ile Leu Glu Ala Val Leu His Cys His Gln

115 120 125

Met Gly Val Val His Arg Asp Leu Lys Pro Glu Asn Leu Leu Leu Ala

130 135 140

Ser Lys Leu Lys Gly Ala Ala Val Lys Leu Ala Asp Phe Gly Leu Ala

145 150 155 160

Ile Glu Val Glu Gly Glu Gln Gln Ala Trp Phe Gly Phe Ala Gly Thr

165 170 175

Pro Gly Tyr Leu Ser Pro Glu Val Leu Arg Lys Asp Pro Tyr Gly Lys

180 185 190

Pro Val Asp Leu Trp Ala Cys Gly Val Ile Leu Tyr Ile Leu Leu Val

195 200 205

Gly Tyr Pro Pro Phe Trp Asp Glu Asp Gln His Arg Leu Tyr Gln Gln

210 215 220

Ile Lys Ala Gly Ala Tyr Asp Phe Pro Ser Pro Glu Trp Asp Thr Val

225 230 235 240

Thr Pro Glu Ala Lys Asp Leu Ile Asn Lys Met Leu Thr Ile Asn Pro

245 250 255

Ser Lys Arg Ile Thr Ala Ala Glu Ala Leu Lys His Pro Trp Ile Ser

260 265 270

His Arg Ser Thr Val Ala Ser Cys Met His Arg Gln Glu Thr Val Asp

275 280 285

Cys Leu Lys Lys Phe Asn Ala Arg Arg Lys Leu Lys Gly Ala Ile Leu

290 295 300

Thr Thr Met Leu Ala Thr Arg Asn Phe Ser Gly Gly Lys Ser Gly Gly

305 310 315 320

Asn Lys Lys Ser Asp Gly Val Lys Lys Arg Lys Ser Ser Ser Ser Val

325 330 335

Gln Leu Met Glu Ser Ser Glu Ser Thr Asn Thr Thr Ile Glu Asp Glu

340 345 350

Asp Thr Lys Val Arg Lys Gln Glu Ile Ile Lys Val Thr Glu Gln Leu

355 360 365

Ile Glu Ala Ile Ser Asn Gly Asp Phe Glu Ser Tyr Thr Lys Met Cys

370 375 380

Asp Pro Gly Met Thr Ala Phe Glu Pro Glu Ala Leu Gly Asn Leu Val

385 390 395 400

Glu Gly Leu Asp Phe His Arg Phe Tyr Phe Glu Asn Leu Trp Ser Arg

405 410 415

Asn Ser Lys Pro Val His Thr Thr Ile Leu Asn Pro His Ile His Leu

420 425 430

Met Gly Asp Glu Ser Ala Cys Ile Ala Tyr Ile Arg Ile Thr Gln Tyr

435 440 445

Leu Asp Ala Gly Gly Ile Pro Arg Thr Ala Gln Ser Glu Glu Thr Arg

450 455 460

Val Trp His Arg Arg Asp Gly Lys Trp Gln Ile Val His Phe His Arg

465 470 475 480

Ser Gly Ala Pro Ser Val Leu Pro His

485

<210> SEQ ID NO: 35

<211> LENGTH: 4586

<212> TYPE: DNA

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic

<400> SEQENCE: 35

aggtgtgcgg cgcgctcctg gcgaggacgg agcgagcaga tctcgcgtgc gctcgccgcc 60

cggcgcagcc cagcccggcc cccgcctggc gccgcgagcc gaggtgtctc ccgcgcccgc 120

gcccgtgtcg ccgccgtgcc cgcgagcggg agccggagtc gccgccgccc gagcgcagcc 180

gagcgcacgc cgagcccgtc cgccgccgcc atggccacca cggtgacctg cacccgcttc 240

accgacgagt accagctcta cgaggatatt ggcaaggggg ctttctctgt ggtccgacgc 300

tgtgtcaagc tctgcaccgg ccatgagtat gcagccaaga tcatcaacac caagaagctg 360

tcagccagag atcaccagaa gctggagaga gaggctcgga tctgccgcct tctgaagcat 420

tccaacatcg tgcgtctcca cgacagcatc tccgaggagg gcttccacta cctggtcttc 480

gatctggtca ctggtgggga gctctttgaa gacattgtgg cgagagagta ctacagcgag 540

gctgatgcca gtcactgtat ccagcagatc ctggaggccg ttctccattg tcaccaaatg 600

ggggtcgtcc acagagacct caagccggag aacctgcttc tggccagcaa gtgcaaaggg 660

gctgcagtga agctggcaga cttcggccta gctatcgagg tgcaggggga ccagcaggca 720

tggtttggtt tcgctggcac accaggctac ctgtcccctg aggtccttcg caaagaggcg 780

tatggcaagc ctgtggacat ctgggcatgt ggggtgatcc tgtacatcct gctcgtgggc 840

tacccaccct tctgggacga ggaccagcac aagctgtacc agcagatcaa ggctggtgcc 900

tatgacttcc cgtcccctga gtgggacacc gtcactcctg aagccaaaaa cctcatcaac 960

cagatgctga ccatcaaccc tgccaagcgc atcacagccc atgaggccct gaagcacccg 1020

tgggtctgcc aacgctccac ggtagcatcc atgatgcaca gacaggagac tgtggagtgt 1080

ctgaaaaagt tcaatgccag gagaaagctc aagggagcca tcctcaccac catgctggcc 1140

acacggaatt tctcagtggg cagacagacc accgctccgg ccacaatgtc caccgcggcc 1200

tccggcacca ccatggggct ggtggaacaa gccaagagtt tactcaacaa gaaagcagat 1260

ggagtcaagc cccagacgaa tagcaccaaa aacagtgcag ccgccaccag ccccaaaggg 1320

acgcttcctc ctgccgccct ggagcctcaa accaccgtca tccataaccc agtggacggg 1380

attaaggagt cttctgacag tgccaatacc accatagagg atgaagacgc taaagccccc 1440

agggtccccg acatcctgag ctcagtgagg aggggctcgg gagccccaga agccgagggg 1500

cccctgccct gcccatctcc ggctcccttt agccccctgc cagccccatc ccccaggatc 1560

tctgacatcc tgaactctgt gagaaggggt tcaggaaccc cagaagccga gggccccctc 1620

tcagcggggc ccccgccctg cctgtctccg gctctcctag gccccctgtc ctccccgtcc 1680

cccaggatct ctgacatcct gaactctgtg aggaggggct cagggacccc agaagccgag 1740

ggcccctcgc cagtggggcc cccgccctgc ccatctccga ctatccctgg ccccctgccc 1800

accccatccc ggaagcagga gatcattaag accacggagc agctcatcga ggccgtcaac 1860

aacggtgact ttgaggccta cgcgaaaatc tgtgacccag ggctgacctc gtttgagcct 1920

gaagcactgg gcaacctggt tgaagggatg gacttccaca gattctactt cgagaacctg 1980

ctggccaaga acagcaagcc gatccacacg accatcctga acccacacgt gcacgtcatt 2040

ggagaggatg ccgcctgcat cgcttacatc cggctcacgc agtacattga cgggcagggc 2100

cggccccgca ccagccagtc tgaggagacc cgcgtgtggc accgccgcga cggcaagtgg 2160

cagaacgtgc acttccactg ctcgggcgcg cctgtggccc cgctgcagtg aagagctgcg 2220

ccctggtttc gccggacaga gttggtgttt ggagcccgac tgccctcggg cacacggcct 2280

gcctgtcgca tgtttgtgtc tgcctcgttc cctcccctgg tgcctgtgtc tgcagaaaaa 2340

caagaccaga tgtgatttgt taaaaaaaaa caaaaaaaaa aaaaaaaaaa acaagatgac 2400

gacgacaacc acaaaaaaaa ttgacatcag atgaaatgaa aaaaaaaaaa aacaaaaaaa 2460

actaaaggaa ggaaaaagct gtaaaaatca ctggcattcg tggggccact ccccacccaa 2520

gctccacgtg tgtccgtctg tgctcctggc ctctggggga ccagctggga catgaacttg 2580

tctgccaggc ccccgtcgcg tgctgaacgg tgttagtttg taggtaacgc acacacccca 2640

cacctaaggt gtctgcatcc tcctgccaac gcatgggctc cacgtggtgt gctcgctggc 2700

tgtcgtgact gtcagctgtc tcttgggagg ggctgtgggg gcccgctggg ctgcctcctt 2760

tcccgctagt tgtgcctgag agttgctgtt gttcctgctt tcccttccct tcctttcatc 2820

ccctgaaggg ctaggtgtgg gttttccgtg cccggtatcc ccacacaccc agcacggaca 2880

acccttcggc agagcccagg ccggcccctc accccctgga gtattgaaac tggagtcccg 2940

tccccaaggc cttcagagat gcccctacac acccagggct ccagctctgg tccttctggg 3000

ggagtaaagt gcaaagaggg gcacagctta gttttgggcc tctcgccgag caagagacag 3060

cactgctggc tacagctcca acacagccag ctgtggcaag aggactctgc ctgggctggc 3120

ccccctcctg tgtgaggtgt ctgtcccttc tctgctggcc agcagcagat gcactggcag 3180

ctcccaaccc tgtttccgcc cctcggccct cccccagcct gttcggcttc tctgcagccc 3240

gcaaggggga gcagactttt gacaaaggac tgcgggcctc gctcaagtcc ctgagccccc 3300

agctgaagct gggaggggag gccaggcttt gtgtctgggc atattcgtct gctgatgggg 3360

tttggggaag cctggggctt ggggtttggt cgggtggtgc agctagtggc agagcgggat 3420

cagaggtggt ggctgcccag cttctgggct gagacaaggg tctgtgcagg ggtttactga 3480

agtgggagtg cctttggaat ctgggccggg agcagaaggg agcaaaagct acagtgggag 3540

ccagcctagg gcacatggga ggcgtgaggg cagtgctgcc cgtgcagtgt caggtgtgcc 3600

agtgccttgg cgggctgcag tgcgtgtgag ggcaccttct aggtgggcca gggatgcagc 3660

tatggagata aggcgggctg gggacagaaa caggtgggca cagggcccag gacaccagcg 3720

gatggagggc agggtctagc cctgtgctcc tgagcgtcgg ctgcctgggt tcgaggcggt 3780

gggtccccgg ccccttgtga tggtgtgtac catgggggag ctcggggaca gggcaagccc 3840

gagcatggtg gggctgcagg gtgggtctga agccaggttg ggtgggggtg gtcacaagcc 3900

ctgactgcag agggtcaggg gctcctgccc cagtgcctgc ccactttcaa ttcacattgt 3960

tttcaacaag gattttcttt atcttcccct acaaatcaag ccaagggagg ggcacagaat 4020

ggggaacagg acacaggatc ctaaactcca aggggactgt ccaccgatga acactcagag 4080

tggacaccat cttccgtcca cgctgtgccc aggacagctg tccccatcca tgaacacagg 4140

gtaaacatct gccgggctcc gcaccagtgg ctccctgggc catgggacag cggcagggct 4200

caccacggac agcacgtggc ccagcagccg gccaccctgg cgtcctgggg cctcctcccc 4260

tcctctccct ctcaccttgt cacctccacg gagctgcctg tctgggataa tttggggatt 4320

ttttttctgg gggataattc ttttgcatga cccctaaaga gcaagccaca ccggtctgct 4380

agctaggtgt ccgcggtgtg gtggtggcgg ccgctggcca gcgctgcaag gggtcggctg 4440

cccacggtgc tggctggcct cccctcctct ctctttttgc tgagtttcat tgtcttttct 4500

ttctgagcct tgtaagtgta caaaaattat tcttattttg ttctgtctcg ggaaactgca 4560

aataaaagaa aaacaggaca aactgc 4586

<210> SEQ ID NO: 36

<211> LENGTH: 666

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic

<400> SEQENCE: 36

Met Ala Thr Thr Val Thr Cys Thr Arg Phe Thr Asp Glu Tyr Gln Leu

1 5 10 15

Tyr Glu Asp Ile Gly Lys Gly Ala Phe Ser Val Val Arg Arg Cys Val

20 25 30

Lys Leu Cys Thr Gly His Glu Tyr Ala Ala Lys Ile Ile Asn Thr Lys

35 40 45

Lys Leu Ser Ala Arg Asp His Gln Lys Leu Glu Arg Glu Ala Arg Ile

50 55 60

Cys Arg Leu Leu Lys His Ser Asn Ile Val Arg Leu His Asp Ser Ile

65 70 75 80

Ser Glu Glu Gly Phe His Tyr Leu Val Phe Asp Leu Val Thr Gly Gly

85 90 95

Glu Leu Phe Glu Asp Ile Val Ala Arg Glu Tyr Tyr Ser Glu Ala Asp

100 105 110

Ala Ser His Cys Ile Gln Gln Ile Leu Glu Ala Val Leu His Cys His

115 120 125

Gln Met Gly Val Val His Arg Asp Leu Lys Pro Glu Asn Leu Leu Leu

130 135 140

Ala Ser Lys Cys Lys Gly Ala Ala Val Lys Leu Ala Asp Phe Gly Leu

145 150 155 160

Ala Ile Glu Val Gln Gly Asp Gln Gln Ala Trp Phe Gly Phe Ala Gly

165 170 175

Thr Pro Gly Tyr Leu Ser Pro Glu Val Leu Arg Lys Glu Ala Tyr Gly

180 185 190

Lys Pro Val Asp Ile Trp Ala Cys Gly Val Ile Leu Tyr Ile Leu Leu

195 200 205

Val Gly Tyr Pro Pro Phe Trp Asp Glu Asp Gln His Lys Leu Tyr Gln

210 215 220

Gln Ile Lys Ala Gly Ala Tyr Asp Phe Pro Ser Pro Glu Trp Asp Thr

225 230 235 240

Val Thr Pro Glu Ala Lys Asn Leu Ile Asn Gln Met Leu Thr Ile Asn

245 250 255

Pro Ala Lys Arg Ile Thr Ala His Glu Ala Leu Lys His Pro Trp Val

260 265 270

Cys Gln Arg Ser Thr Val Ala Ser Met Met His Arg Gln Glu Thr Val

275 280 285

Glu Cys Leu Lys Lys Phe Asn Ala Arg Arg Lys Leu Lys Gly Ala Ile

290 295 300

Leu Thr Thr Met Leu Ala Thr Arg Asn Phe Ser Val Gly Arg Gln Thr

305 310 315 320

Thr Ala Pro Ala Thr Met Ser Thr Ala Ala Ser Gly Thr Thr Met Gly

325 330 335

Leu Val Glu Gln Ala Lys Ser Leu Leu Asn Lys Lys Ala Asp Gly Val

340 345 350

Lys Pro Gln Thr Asn Ser Thr Lys Asn Ser Ala Ala Ala Thr Ser Pro

355 360 365

Lys Gly Thr Leu Pro Pro Ala Ala Leu Glu Pro Gln Thr Thr Val Ile

370 375 380

His Asn Pro Val Asp Gly Ile Lys Glu Ser Ser Asp Ser Ala Asn Thr

385 390 395 400

Thr Ile Glu Asp Glu Asp Ala Lys Ala Pro Arg Val Pro Asp Ile Leu

405 410 415

Ser Ser Val Arg Arg Gly Ser Gly Ala Pro Glu Ala Glu Gly Pro Leu

420 425 430

Pro Cys Pro Ser Pro Ala Pro Phe Ser Pro Leu Pro Ala Pro Ser Pro

435 440 445

Arg Ile Ser Asp Ile Leu Asn Ser Val Arg Arg Gly Ser Gly Thr Pro

450 455 460

Glu Ala Glu Gly Pro Leu Ser Ala Gly Pro Pro Pro Cys Leu Ser Pro

465 470 475 480

Ala Leu Leu Gly Pro Leu Ser Ser Pro Ser Pro Arg Ile Ser Asp Ile

485 490 495

Leu Asn Ser Val Arg Arg Gly Ser Gly Thr Pro Glu Ala Glu Gly Pro

500 505 510

Ser Pro Val Gly Pro Pro Pro Cys Pro Ser Pro Thr Ile Pro Gly Pro

515 520 525

Leu Pro Thr Pro Ser Arg Lys Gln Glu Ile Ile Lys Thr Thr Glu Gln

530 535 540

Leu Ile Glu Ala Val Asn Asn Gly Asp Phe Glu Ala Tyr Ala Lys Ile

545 550 555 560

Cys Asp Pro Gly Leu Thr Ser Phe Glu Pro Glu Ala Leu Gly Asn Leu

565 570 575

Val Glu Gly Met Asp Phe His Arg Phe Tyr Phe Glu Asn Leu Leu Ala

580 585 590

Lys Asn Ser Lys Pro Ile His Thr Thr Ile Leu Asn Pro His Val His

595 600 605

Val Ile Gly Glu Asp Ala Ala Cys Ile Ala Tyr Ile Arg Leu Thr Gln

610 615 620

Tyr Ile Asp Gly Gln Gly Arg Pro Arg Thr Ser Gln Ser Glu Glu Thr

625 630 635 640

Arg Val Trp His Arg Arg Asp Gly Lys Trp Gln Asn Val His Phe His

645 650 655

Cys Ser Gly Ala Pro Val Ala Pro Leu Gln

660 665

<210> SEQ ID NO: 37

<211> LENGTH: 5820

<212> TYPE: DNA

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic

<400> SEQENCE: 37

aaaggaggga gtgcgagaga tccacgaagg gacaggcttg gagtcgctag agggaggtgt 60

gggaccagcg aggagggggc ttcgccaggg agggggtgct ggcaggcgga gggagcggcg 120

ggaggaggcg ccggaggagg agacggaggc ctggggacgg cagaagaggc ttcgcctgag 180

ccgagcgctc tttctctcgc cgcgccgtct tgaagccgcg cgggctcgtg agcagcgcga 240

ggccgccaag gtgcctcgct tcgccggagc cgctgccgcc cgccggaggg aagccggcct 300

cgggcgcgca cgctcgtcgg agccccggcg cgccccgcgc ctgagcctgc tgacagcggc 360

cgctgggctc aggctgtccg ctctgggctc cgcggcctcg gccccgctgc actccacctc 420

cgccccctcg gactccctcc cctctgcttc tactcctcct gctccagtgc ggatcgtttc 480

gcaactgctt gccactcgtc ccgtgcctgg ctgtttttcc atttcccggc cccctcttct 540

tgagtacttt accccctgca tttggggaca gggactggaa aaggggcggg tggagcgtcc 600

agtggagaag aaggaagcga ggcccgcagg aggaggagga tcggcggact gtggggagga 660

gaccccacgc caccctttct ggtcatctcc cctcccgccc cgcccctgcg cacactccct 720

cgcgggcgag ctactttcgg accaggaaag taagagcggc cctgggtgac agcgccgcgg 780

ggccagtccc ggggttagcc gcgcgtctgc tcgcttctgg tccgtcgcgc tcccagccag 840

ggcacagccc ggaccgagga tggcttcgac cacaacctgc accaggttca cggacgagta 900

tcagcttttc gaggagcttg gaaagggggc attctcagtg gtgagaagat gtatgaaaat 960

tcctactgga caagaatatg ctgccaaaat tatcaacacc aaaaagcttt ctgctaggga 1020

tcatcagaaa ctagaaagag aagctagaat ctgccgtctt ttgaagcacc ctaatattgt 1080

gcgacttcat gatagcatat cagaagaggg ctttcactac ttggtgtttg atttagttac 1140

tggaggtgaa ctgtttgaag acatagtggc aagagaatac tacagtgaag ctgatgccag 1200

tcattgtata cagcagattc tagaaagtgt taatcattgt cacctaaatg gcatagttca 1260

cagggacctg aagcctgaga atttgctttt agctagcaaa tccaagggag cagctgtgaa 1320

attggcagac tttggcttag ccatagaagt tcaaggggac cagcaggcgt ggtttggttt 1380

tgctggcaca cctggatatc tttctccaga agttttacgt aaagatcctt atggaaagcc 1440

agtggatatg tgggcatgtg gtgtcattct ctatattcta cttgtggggt atccaccctt 1500

ctgggatgaa gaccaacaca gactctatca gcagatcaag gctggagctt atgattttcc 1560

atcaccagaa tgggacacgg tgactcctga agccaaagac ctcatcaata aaatgcttac 1620

tatcaaccct gccaaacgca tcacagcctc agaggcactg aagcacccat ggatctgtca 1680

acgttctact gttgcttcca tgatgcacag acaggagact gtagactgct tgaagaaatt 1740

taatgctaga agaaaactaa agggtgccat cttgacaact atgctggcta caaggaattt 1800

ctcagcagcc aagagtttgt tgaagaaacc agatggagta aaggagtcaa ctgagagttc 1860

aaatacaaca attgaggatg aagatgtgaa agcacgaaag caagagatta tcaaagtcac 1920

tgaacaactg atcgaagcta tcaacaatgg ggactttgaa gcctacacaa aaatctgtga 1980

cccaggcctt actgcttttg aacctgaagc tttgggtaat ttagtggaag ggatggattt 2040

tcaccgattc tactttgaaa atgctttgtc caaaagcaat aaaccaatcc acactattat 2100

tctaaaccct catgtacatc tggtagggga tgatgccgcc tgcatagcat atattaggct 2160

cacacagtac atggatggca gtggaatgcc aaagacaatg cagtcagaag agactcgtgt 2220

gtggcaccgc cgggatggaa agtggcagaa tgttcatttt catcgctcgg ggtcaccaac 2280

agtacccatc aagtaaatat ttccaggctg tcagcttctt tgttaataca cccatgctaa 2340

atttcaacag tgccacttct gcattctctg ttctcaaggc acctggatgg tgaccctggg 2400

ccgtcctctc ctcctcttca tgcatgtttc tgagtgcatg aagttgtgaa ggtcctacat 2460

gtaatgcata tgtgatgcat catcttatca tatattcctt cctatacatt gtttacactt 2520

caactacggg gatgttccac acaaacttaa attactgttg gcaaaacaat agggggagat 2580

tagacaaaaa aaaaaatcca caatattcca agtacaactc ttcatcaagt ttctctgtta 2640

atgccaagat ttaacagact taagaactat tgttctctga atgacagttg taagagaaat 2700

gtaaattttt tagaactctt tgctgttaat ctgttttggt ttgtttggtt tttttttttt 2760

tttttaaggt aaaaaaaaaa tacaccttca gtttcctggt gtgatcctgg ttaaaatgga 2820

tgatttttca ttgaaagttt tgctgattaa caattaaagt gggatgatat gtgggcaaaa 2880

tcacttatga aagtagaagc aagaatcagt tggtttgcta ccacataaag ccatgctgtt 2940

tttggtcaaa ctgtgtaaac tggaaaaatt cacatcattt ctgagtttaa tcactttagg 3000

atatattcac attgttttgg tgaatttgct gaattgaatt gtttttcttt ctcaaatctg 3060

tgatctcttt tctttatcct gtttctttgt tcctttcgtt tgctttctta tttttctttt 3120

gttccattct tttcttactt ttttcccttt tccttttttg gggaggctgg ctagtagtgt 3180

gtgagaaaag aatagaagtg aaatttgcat aatgaatgta aaagggaaat aaaagtcttt 3240

tgaaggtagc tatactagca cttttgatca tcttcagggc ccacaaaaat gttgtcaaga 3300

ttttaaaggt ttataattct gcttaagctc tagtttggac ttaggtatcc taactatgtt 3360

ggaggtattt gcattgttta aagttaggat aaaagcaagt tcctcctgtg actgcaacgt 3420

cttactgatt gggacagttg ccaggaggat accaacttga tagcagaggg ggttttatgc 3480

aaacgcactc acctccgcct tggggaatga aagggtcact tctgcatcat cactagctag 3540

ttttctagtg ttagagaggc ttacaaatgt ttgccattct cataagtgtt ttgaacttga 3600

tctttgtgac ttgtgctttt ttagcttctc tcttgaatca gagtatcatt gtcttcctcc 3660

aaggagttag aatttcccag tttaaaacaa aaagggaaat gtcctaggtt ttctttgtgc 3720

ttctcatttt tcctttgttg attcaattcc tgtgattttt gttctcttcc ctgaagtgct 3780

ttacagtgca tggaatctcc atcattgtta ttttaacgat agtaattcac agtcctcaga 3840

agcctatttt taaagcagaa gcaaaaaaga aaaacaaaat aacaaaaaca acccttcctc 3900

ttttctctca tctcacctct ctgtgttgat tactaatcat cttagatatt attgctagtg 3960

gatgtatggt agatgggttg aagcttttct gataattatt acacaattta aaacaacata 4020

tatatttaaa ataaatatat acagtaaata tattgagcca tgttaacctg ccaatgagat 4080

ctgtgaaaaa ataatggcct catttttctc tttttaattt cttttaccct tttgtgaagc 4140

agctatacgt ggcatacatg tatttaaaga aaaaaaaata gatgtagagt gtttttttta 4200

cacttttaac ttagcatgtg gtgttgaagt attactgtag atcaagtttg tcttccgcac 4260

taagatgtga ggaaattgtg atttgttctc tccaccacaa atgaattaca catttattat 4320

cttctatcat tttgaaacac tgcagtttac catgggacac tgtatatatt tcttgccata 4380

atggtaaagg actgattgat atatttaaga gttaataaat ttgtgatttc tgctgacagt 4440

gcgtccatct ttatttcttc agaagaggta ctgtatgtat gcctgcatag tgctggccag 4500

tgtcaagggc agtgtgtcct actctggtct catttagtac ataacaattt gcacttggtg 4560

agaatggcaa gttaattgtt ctctgtgagc aaaacaatgg tctcttctgg gaaaatgttg 4620

ctgagaacaa tatagttaac aactaagact cctaaaagct tctctaaact gtaccctcca 4680

atccagcctt cacatggctg cttttttttt ttttttttaa tacgaacctg tccttgtaac 4740

actttgatgt tatcatttct gggatacagg caagcacccc agctcctgct actccccagc 4800

ttgaacttga gcatacatgg atgctcagct tcttttgatt tgctaaaaac atcacacttg 4860

ctcacatgcc tgtttatgct gttcatgttg tttatgtttc ttacctagaa taaatagtct 4920

cttcccctac ttcttttccc gacttcttac tttttcctaa gattcagtgt acagcatcat 4980

gctccacagc aaaccttcct aggccctatt ctgggcttgc cttccctctc aaaacctaca 5040

taatagattg tatttacctc tcctgtcaac cacattgttt tgaaaatata tttctatttg 5100

tgtctcctct actgcagtat aatgtctcca tgggcaagaa ctgtgtattc atcattgcat 5160

tcctaaaccc aaaccaaggc caggaatgga gatatcattg ataaatagtt gttgaattga 5220

ggccaagccc ttttgataac agaagcctca aggggtaccc agatagtcct tgttttaatg 5280

atgggttctc tcaccactgt cttgatgctc tgagcaagtt acctcttccc tctgaccctc 5340

agtttccata tttgtaaaat gagaataaac ataccaactt aataaagata ttgtgaggat 5400

taatgggtac agagtgacta gaatgatatt tgatagaaat taaatggtag cagtataact 5460

attctgatca ctgacattaa tattcctatt gttattattc tttgctcacg agggtataca 5520

actcttgttt tgctgttggg ctgccctctt tatgtaggtt tactgttaat gctgaggata 5580

tactcggact caaatgtctc agcagaaggc tgagagacac caaatgaagt ggtcatctag 5640

ctgaatgtag gaaaaatgaa atgtagtagc aaatcagtat attctaagga aattttcaag 5700

gaatattaat cttcacccaa attttgaatt tttatgtaaa aaattataat ttaagggtaa 5760

acatagatga cacagctttc gagtgatttc attgaataaa attctactga cttctatgaa 5820

<210> SEQ ID NO: 38

<211> LENGTH: 478

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic

<400> SEQENCE: 38

Met Ala Ser Thr Thr Thr Cys Thr Arg Phe Thr Asp Glu Tyr Gln Leu

1 5 10 15

Phe Glu Glu Leu Gly Lys Gly Ala Phe Ser Val Val Arg Arg Cys Met

20 25 30

Lys Ile Pro Thr Gly Gln Glu Tyr Ala Ala Lys Ile Ile Asn Thr Lys

35 40 45

Lys Leu Ser Ala Arg Asp His Gln Lys Leu Glu Arg Glu Ala Arg Ile

50 55 60

Cys Arg Leu Leu Lys His Pro Asn Ile Val Arg Leu His Asp Ser Ile

65 70 75 80

Ser Glu Glu Gly Phe His Tyr Leu Val Phe Asp Leu Val Thr Gly Gly

85 90 95

Glu Leu Phe Glu Asp Ile Val Ala Arg Glu Tyr Tyr Ser Glu Ala Asp

100 105 110

Ala Ser His Cys Ile Gln Gln Ile Leu Glu Ser Val Asn His Cys His

115 120 125

Leu Asn Gly Ile Val His Arg Asp Leu Lys Pro Glu Asn Leu Leu Leu

130 135 140

Ala Ser Lys Ser Lys Gly Ala Ala Val Lys Leu Ala Asp Phe Gly Leu

145 150 155 160

Ala Ile Glu Val Gln Gly Asp Gln Gln Ala Trp Phe Gly Phe Ala Gly

165 170 175

Thr Pro Gly Tyr Leu Ser Pro Glu Val Leu Arg Lys Asp Pro Tyr Gly

180 185 190

Lys Pro Val Asp Met Trp Ala Cys Gly Val Ile Leu Tyr Ile Leu Leu

195 200 205

Val Gly Tyr Pro Pro Phe Trp Asp Glu Asp Gln His Arg Leu Tyr Gln

210 215 220

Gln Ile Lys Ala Gly Ala Tyr Asp Phe Pro Ser Pro Glu Trp Asp Thr

225 230 235 240

Val Thr Pro Glu Ala Lys Asp Leu Ile Asn Lys Met Leu Thr Ile Asn

245 250 255

Pro Ala Lys Arg Ile Thr Ala Ser Glu Ala Leu Lys His Pro Trp Ile

260 265 270

Cys Gln Arg Ser Thr Val Ala Ser Met Met His Arg Gln Glu Thr Val

275 280 285

Asp Cys Leu Lys Lys Phe Asn Ala Arg Arg Lys Leu Lys Gly Ala Ile

290 295 300

Leu Thr Thr Met Leu Ala Thr Arg Asn Phe Ser Ala Ala Lys Ser Leu

305 310 315 320

Leu Lys Lys Pro Asp Gly Val Lys Glu Ser Thr Glu Ser Ser Asn Thr

325 330 335

Thr Ile Glu Asp Glu Asp Val Lys Ala Arg Lys Gln Glu Ile Ile Lys

340 345 350

Val Thr Glu Gln Leu Ile Glu Ala Ile Asn Asn Gly Asp Phe Glu Ala

355 360 365

Tyr Thr Lys Ile Cys Asp Pro Gly Leu Thr Ala Phe Glu Pro Glu Ala

370 375 380

Leu Gly Asn Leu Val Glu Gly Met Asp Phe His Arg Phe Tyr Phe Glu

385 390 395 400

Asn Ala Leu Ser Lys Ser Asn Lys Pro Ile His Thr Ile Ile Leu Asn

405 410 415

Pro His Val His Leu Val Gly Asp Asp Ala Ala Cys Ile Ala Tyr Ile

420 425 430

Arg Leu Thr Gln Tyr Met Asp Gly Ser Gly Met Pro Lys Thr Met Gln

435 440 445

Ser Glu Glu Thr Arg Val Trp His Arg Arg Asp Gly Lys Trp Gln Asn

450 455 460

Val His Phe His Arg Ser Gly Ser Pro Thr Val Pro Ile Lys

465 470 475

<210> SEQ ID NO: 39

<211> LENGTH: 3821

<212> TYPE: DNA

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic

<400> SEQENCE: 39

agtctcgcgg tgctgccggg ctcagccccg tctcctcctc ttgctccctc ggccgggcgg 60

cggtgactgt gcaccgacgt cggcgcgggc tgcaccgccg cgtccgcccg cccgccagca 120

tggccaccac cgccacctgc acccgtttca ccgacgacta ccagctcttc gaggagcttg 180

gcaagggtgc tttctctgtg gtccgcaggt gtgtgaagaa aacctccacg caggagtacg 240

cagcaaaaat catcaatacc aagaagttgt ctgcccggga tcaccagaaa ctagaacgtg 300

aggctcggat atgtcgactt ctgaaacatc caaacatcgt gcgcctccat gacagtattt 360

ctgaagaagg gtttcactac ctcgtgtttg accttgttac cggcggggag ctgtttgaag 420

acattgtggc cagagagtac tacagtgaag cagatgccag ccactgtata catcagattc 480

tggagagtgt taaccacatc caccagcatg acatcgtcca cagggacctg aagcctgaga 540

acctgctgct ggcgagtaaa tgcaagggtg ccgccgtcaa gctggctgat tttggcctag 600

ccatcgaagt acagggagag cagcaggctt ggtttggttt tgctggcacc ccaggttact 660

tgtcccctga ggtcttgagg aaagatccct atggaaaacc tgtggatatc tgggcctgcg 720

gggtcatcct gtatatcctc ctggtgggct atcctccctt ctgggatgag gatcagcaca 780

agctgtatca gcagatcaag gctggagcct atgatttccc atcaccagaa tgggacacgg 840

taactcctga agccaagaac ttgatcaacc agatgctgac cataaaccca gcaaagcgca 900

tcacggctga ccaggctctc aagcacccgt gggtctgtca acgatccacg gtggcatcca 960

tgatgcatcg tcaggagact gtggagtgtt tgcgcaagtt caatgcccgg agaaaactga 1020

agggtgccat cctcacgacc atgcttgtct ccaggaactt ctcagctgcc aaaagcctat 1080

tgaacaagaa gtcggatggc ggtgtcaagc cacagagcaa caacaaaaac agtctcgtaa 1140

gcccagccca agagcccgcg cccttgcaga cggccatgga gccacaaacc actgtggtac 1200

acaacgctac agatgggatc aagggctcca cagagagctg caacaccacc acagaagatg 1260

aggacctcaa agctgccccg ctccgcactg ggaatggcag ctcggtgcct gaaggacgga 1320

gctcccggga cagaacagcc ccctctgcag gcatgcagcc ccagccttct ctctgctcct 1380

cagccatgcg aaaacaggag atcattaaga ttacagaaca gctgattgaa gccatcaaca 1440

atggggactt tgaggcctac acgaagattt gtgatccagg cctcacttcc tttgagcctg 1500

aggcccttgg taacctcgtg gaggggatgg atttccataa gttttacttt gagaatctcc 1560

tgtccaagaa cagcaagcct atccatacca ccatcctaaa cccacacgtc cacgtgattg 1620

gggaggacgc agcgtgcatc gcctacatcc gcctcaccca gtacatcgac gggcagggtc 1680

ggcctcgcac cagccagtca gaagagaccc gggtctggca ccgtcgggat ggcaagtggc 1740

tcaatgtcca ctatcactgc tcaggggccc ctgccgcacc gctgcagtga gctcagccac 1800

aggggcttta ggagattcca gccggaggtc caaccttcgc agccagtggc tctggagggc 1860

ctgagtgaca gcggcagtcc tgtttgtttg aggtttaaaa caattcaatt acaaaagcgg 1920

cagcagccaa tgcacgcccc tgcatgcagc cctcccgccc gcccttcgtg tctgtctctg 1980

ctgtaccgag gtgtttttta catttaagaa aaaaaaaaaa gaaaaaaaga ttgtttaaaa 2040

aaaaaaggaa tccataccat gatgcgtttt aaaaccaccg acagcccttg ggttggcaag 2100

aaggcaggag tatgtatgag gtccatcctg gcatgagcag tggctcaccc accggccttg 2160

aagaggtgag cttggcctct ctggtcccca tggacttagg gggaccaggc aagaactctg 2220

acagagcttt gggggccgtg atgtgattgc agctcctgag gtggcctgct taccccaggt 2280

ctaggaatga acttctttgg aacttgcata ggcgcctaga atggggctga tgagaacatc 2340

gtgaccatca gacctacttg ggagagaacg cagagctccc agcctgctgt ggaggcagct 2400

gagaagtggt ggcctcagga ctgagagccc ggacgttgct gtactgtctt gtttagtgta 2460

gaagggaaga gaattggtgc tgcagaagtg tacccgccat gaagccgatg agaaacctcg 2520

tgttagtctg acatgcactc actcatccat ttctatagga tgcacaatgc atgtgggccc 2580

taatattgag gccttatccc tgcagctagg agggggaggg gttgttgctg ctttgcttcg 2640

tgttttcttc taacctggca aggagagagc caggccctgg tcagggctcc cgtgccgcct 2700

ttggcggttc tgtttctgtg ctgatctgga ccatctttgt cttgcctttt cacggtagtg 2760

gtccccatgc tgaccctcat ctgggcctgg gccctctgcc aagtgcccct gtgggatggg 2820

aggagtgagg cagtgggaga agaggtggtg gtcgtttcta tgcattcagg ctgcctttgg 2880

ggctgcctcc cttcttattc ttccttgctg cacgtccatc tcttttcctg tctttgagat 2940

tgacctgact gctctggcaa gaagaagagg tgtccttaca gaggcctctt tactgaccaa 3000

ctgaagtata gacttactgc tggacaatct gcatgggcat cacccctccc cgcatgtaac 3060

ccaaaagagg tgtccagagc caaggcttct accttcattg tccctctctg tgctcaagga 3120

gttccattcc aggaggaaga gatctatacc ctaagcagat agcaaagaag ataatggagg 3180

agcaattggt catggccttg gtttccctca aaacaacgct gcagatttat ctgcacaaac 3240

atctccactt ttgggggaaa ggtgggtaga ttccagttcc ctggactacc ttcaggaggc 3300

acgagagctg ggagaagagg caaagctaca ggtttacttg ggagccagct gagaagagag 3360

cagactcaca ggtgctggtg cttggattta gccaggctcc tccgagcacc tcatgcatgt 3420

cccagcccct gggccctagc cctttcctgc cctgcagtct gcagtgccag cacgcaaatc 3480

ccttcaccac agggtttcgt tttgctggct tgaagacaaa tggtcttaga attcattgag 3540

acccatagct tcatatggct gctccagccc cacttcttag cattcttact cctcttctgg 3600

ggctaatgtc agcatctata gacaatagac tattaaaaaa tcacctttta aacaagaaac 3660

ggaaggcatt tgatgcagaa tttttgcatg acaacataga aataatttaa aaatagtgtt 3720

tgttctgaat gttggtagac ccttcatagc tttgttacaa tgaaaccttg aactgaaaat 3780

atttaataaa ataaccttta aacagtcaaa aaaaaaaaaa a 3821

<210> SEQ ID NO: 40

<211> LENGTH: 556

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic

<400> SEQENCE: 40

Met Ala Thr Thr Ala Thr Cys Thr Arg Phe Thr Asp Asp Tyr Gln Leu

1 5 10 15

Phe Glu Glu Leu Gly Lys Gly Ala Phe Ser Val Val Arg Arg Cys Val

20 25 30

Lys Lys Thr Ser Thr Gln Glu Tyr Ala Ala Lys Ile Ile Asn Thr Lys

35 40 45

Lys Leu Ser Ala Arg Asp His Gln Lys Leu Glu Arg Glu Ala Arg Ile

50 55 60

Cys Arg Leu Leu Lys His Pro Asn Ile Val Arg Leu His Asp Ser Ile

65 70 75 80

Ser Glu Glu Gly Phe His Tyr Leu Val Phe Asp Leu Val Thr Gly Gly

85 90 95

Glu Leu Phe Glu Asp Ile Val Ala Arg Glu Tyr Tyr Ser Glu Ala Asp

100 105 110

Ala Ser His Cys Ile His Gln Ile Leu Glu Ser Val Asn His Ile His

115 120 125

Gln His Asp Ile Val His Arg Asp Leu Lys Pro Glu Asn Leu Leu Leu

130 135 140

Ala Ser Lys Cys Lys Gly Ala Ala Val Lys Leu Ala Asp Phe Gly Leu

145 150 155 160

Ala Ile Glu Val Gln Gly Glu Gln Gln Ala Trp Phe Gly Phe Ala Gly

165 170 175

Thr Pro Gly Tyr Leu Ser Pro Glu Val Leu Arg Lys Asp Pro Tyr Gly

180 185 190

Lys Pro Val Asp Ile Trp Ala Cys Gly Val Ile Leu Tyr Ile Leu Leu

195 200 205

Val Gly Tyr Pro Pro Phe Trp Asp Glu Asp Gln His Lys Leu Tyr Gln

210 215 220

Gln Ile Lys Ala Gly Ala Tyr Asp Phe Pro Ser Pro Glu Trp Asp Thr

225 230 235 240

Val Thr Pro Glu Ala Lys Asn Leu Ile Asn Gln Met Leu Thr Ile Asn

245 250 255

Pro Ala Lys Arg Ile Thr Ala Asp Gln Ala Leu Lys His Pro Trp Val

260 265 270

Cys Gln Arg Ser Thr Val Ala Ser Met Met His Arg Gln Glu Thr Val

275 280 285

Glu Cys Leu Arg Lys Phe Asn Ala Arg Arg Lys Leu Lys Gly Ala Ile

290 295 300

Leu Thr Thr Met Leu Val Ser Arg Asn Phe Ser Ala Ala Lys Ser Leu

305 310 315 320

Leu Asn Lys Lys Ser Asp Gly Gly Val Lys Pro Gln Ser Asn Asn Lys

325 330 335

Asn Ser Leu Val Ser Pro Ala Gln Glu Pro Ala Pro Leu Gln Thr Ala

340 345 350

Met Glu Pro Gln Thr Thr Val Val His Asn Ala Thr Asp Gly Ile Lys

355 360 365

Gly Ser Thr Glu Ser Cys Asn Thr Thr Thr Glu Asp Glu Asp Leu Lys

370 375 380

Ala Ala Pro Leu Arg Thr Gly Asn Gly Ser Ser Val Pro Glu Gly Arg

385 390 395 400

Ser Ser Arg Asp Arg Thr Ala Pro Ser Ala Gly Met Gln Pro Gln Pro

405 410 415

Ser Leu Cys Ser Ser Ala Met Arg Lys Gln Glu Ile Ile Lys Ile Thr

420 425 430

Glu Gln Leu Ile Glu Ala Ile Asn Asn Gly Asp Phe Glu Ala Tyr Thr

435 440 445

Lys Ile Cys Asp Pro Gly Leu Thr Ser Phe Glu Pro Glu Ala Leu Gly

450 455 460

Asn Leu Val Glu Gly Met Asp Phe His Lys Phe Tyr Phe Glu Asn Leu

465 470 475 480

Leu Ser Lys Asn Ser Lys Pro Ile His Thr Thr Ile Leu Asn Pro His

485 490 495

Val His Val Ile Gly Glu Asp Ala Ala Cys Ile Ala Tyr Ile Arg Leu

500 505 510

Thr Gln Tyr Ile Asp Gly Gln Gly Arg Pro Arg Thr Ser Gln Ser Glu

515 520 525

Glu Thr Arg Val Trp His Arg Arg Asp Gly Lys Trp Leu Asn Val His

530 535 540

Tyr His Cys Ser Gly Ala Pro Ala Ala Pro Leu Gln

545 550 555

<210> SEQ ID NO: 41

<211> LENGTH: 2168

<212> TYPE: DNA

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic

<400> SEQENCE: 41

ctctctcgct cctgcgttcg caggcggcgg ctggcggccg gcttctcgct cgggcagcgg 60

cggcggcggc ggcggcggct tccggagtcc cgctgcgaag atgctcaaag tcacggtgcc 120

ctcctgctcc gcctcgtcct gctcttcggt caccgccagt gcggccccgg ggaccgcgag 180

cctcgtcccg gattactgga tcgacggctc caacagggat gcgctgagcg atttcttcga 240

ggtggagtcg gagctgggac ggggtgctac atccattgtg tacagatgca aacagaaggg 300

gacccagaag ccttatgctc tcaaagtgtt aaagaaaaca gtggacaaaa aaatcgtaag 360

aactgagata ggagttcttc ttcgcctctc acatccaaac attataaaac ttaaagagat 420

atttgaaacc cctacagaaa tcagtctggt cctagaactc gtcacaggag gagaactgtt 480

tgataggatt gtggaaaagg gatattacag tgagcgagat gctgcagatg ccgttaaaca 540

aatcctggag gcagttgctt atctacatga aaatgggatt gtccatcgtg atctcaaacc 600

agagaatctt ctttatgcaa ctccagcccc agatgcacca ctcaaaatcg ctgattttgg 660

actctctaaa attgtggaac atcaagtgct catgaagaca gtatgtggaa ccccagggta 720

ctgcgcacct gaaattctta gaggttgtgc ctatggacct gaggtggaca tgtggtctgt 780

aggaataatc acctacatct tactttgtgg atttgaacca ttctatgatg aaagaggcga 840

tcagttcatg ttcaggagaa ttctgaattg tgaatattac tttatctccc cctggtggga 900

tgaagtatct ctaaatgcca aggacttggt cagaaaatta attgttttgg atccaaagaa 960

acggctgact acatttcaag ctctccagca tccgtgggtc acaggtaaag cagccaattt 1020

tgtacacatg gataccgctc aaaagaagct ccaagaattc aatgcccggc gtaagcttaa 1080

ggcagcggtg aaggctgtgg tggcctcttc gcgcctggga agtgccagca gcagccatgg 1140

cagcatccag gagagccaca aggctagccg agacccttct ccaatccaag atggcaacga 1200

ggacatgaaa gctattccag aaggagagaa aattcaaggc gatggggccc aagccgcagt 1260

taagggggca caggctgagc tgatgaaggt gcaagcctta gagaaagtta aaggtgcaga 1320

tataaatgct gaagaggccc ccaaaatggt gcccaaggca gtggaggatg ggataaaggt 1380

ggctgacctg gaactagagg agggcctagc agaggagaag ctgaagactg tggaggaggc 1440

agcagctccc agagaagggc aaggaagctc tgctgtgggt tttgaagttc cacagcaaga 1500

tgtgatcctg ccagagtact aaacagcttc cttcagatct ggaagccaaa caccggcatt 1560

ttatgtactt tgtccttcag caagaaaggt gtggaagcat gatatgtact atagtgattc 1620

tgtttttgag gtgcaaaaaa catacatata taccagttgg taattctaac ttcaatgcat 1680

gtgactgctt tatgaaaata atagtgtctt ctatggcatg taatggatac ctaataccga 1740

tgagttaaat cttgcaagtt aacacaacgt aacacttaaa agcatacatt ttcagcaacc 1800

agtggcacat atttgaagtg aatagtagca aattgttttt gctttgaaaa tctagccatc 1860

ctacatcctt tggatttctt cacaaggcag taattccttt gaactactgc ttagctaata 1920

ctaggtagtg ctaaaagaca tgttcccata acttttacaa cattttactt tttatcattg 1980

atgtgttcaa actgtttaca aggagatgct tatagatgat agttgtacat atgtgcaaaa 2040

aaaaatccac ttgcaatggt aagaaattga agtatcctta aaggccatga agccatatgt 2100

ccctaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa 2160

aaaaaaaa 2168

<210> SEQ ID NO: 42

<211> LENGTH: 473

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic

<400> SEQENCE: 42

Met Leu Lys Val Thr Val Pro Ser Cys Ser Ala Ser Ser Cys Ser Ser

1 5 10 15

Val Thr Ala Ser Ala Ala Pro Gly Thr Ala Ser Leu Val Pro Asp Tyr

20 25 30

Trp Ile Asp Gly Ser Asn Arg Asp Ala Leu Ser Asp Phe Phe Glu Val

35 40 45

Glu Ser Glu Leu Gly Arg Gly Ala Thr Ser Ile Val Tyr Arg Cys Lys

50 55 60

Gln Lys Gly Thr Gln Lys Pro Tyr Ala Leu Lys Val Leu Lys Lys Thr

65 70 75 80

Val Asp Lys Lys Ile Val Arg Thr Glu Ile Gly Val Leu Leu Arg Leu

85 90 95

Ser His Pro Asn Ile Ile Lys Leu Lys Glu Ile Phe Glu Thr Pro Thr

100 105 110

Glu Ile Ser Leu Val Leu Glu Leu Val Thr Gly Gly Glu Leu Phe Asp

115 120 125

Arg Ile Val Glu Lys Gly Tyr Tyr Ser Glu Arg Asp Ala Ala Asp Ala

130 135 140

Val Lys Gln Ile Leu Glu Ala Val Ala Tyr Leu His Glu Asn Gly Ile

145 150 155 160

Val His Arg Asp Leu Lys Pro Glu Asn Leu Leu Tyr Ala Thr Pro Ala

165 170 175

Pro Asp Ala Pro Leu Lys Ile Ala Asp Phe Gly Leu Ser Lys Ile Val

180 185 190

Glu His Gln Val Leu Met Lys Thr Val Cys Gly Thr Pro Gly Tyr Cys

195 200 205

Ala Pro Glu Ile Leu Arg Gly Cys Ala Tyr Gly Pro Glu Val Asp Met

210 215 220

Trp Ser Val Gly Ile Ile Thr Tyr Ile Leu Leu Cys Gly Phe Glu Pro

225 230 235 240

Phe Tyr Asp Glu Arg Gly Asp Gln Phe Met Phe Arg Arg Ile Leu Asn

245 250 255

Cys Glu Tyr Tyr Phe Ile Ser Pro Trp Trp Asp Glu Val Ser Leu Asn

260 265 270

Ala Lys Asp Leu Val Arg Lys Leu Ile Val Leu Asp Pro Lys Lys Arg

275 280 285

Leu Thr Thr Phe Gln Ala Leu Gln His Pro Trp Val Thr Gly Lys Ala

290 295 300

Ala Asn Phe Val His Met Asp Thr Ala Gln Lys Lys Leu Gln Glu Phe

305 310 315 320

Asn Ala Arg Arg Lys Leu Lys Ala Ala Val Lys Ala Val Val Ala Ser

325 330 335

Ser Arg Leu Gly Ser Ala Ser Ser Ser His Gly Ser Ile Gln Glu Ser

340 345 350

His Lys Ala Ser Arg Asp Pro Ser Pro Ile Gln Asp Gly Asn Glu Asp

355 360 365

Met Lys Ala Ile Pro Glu Gly Glu Lys Ile Gln Gly Asp Gly Ala Gln

370 375 380

Ala Ala Val Lys Gly Ala Gln Ala Glu Leu Met Lys Val Gln Ala Leu

385 390 395 400

Glu Lys Val Lys Gly Ala Asp Ile Asn Ala Glu Glu Ala Pro Lys Met

405 410 415

Val Pro Lys Ala Val Glu Asp Gly Ile Lys Val Ala Asp Leu Glu Leu

420 425 430

Glu Glu Gly Leu Ala Glu Glu Lys Leu Lys Thr Val Glu Glu Ala Ala

435 440 445

Ala Pro Arg Glu Gly Gln Gly Ser Ser Ala Val Gly Phe Glu Val Pro

450 455 460

Gln Gln Asp Val Ile Leu Pro Glu Tyr

465 470

<210> SEQ ID NO: 43

<211> LENGTH: 1522

<212> TYPE: DNA

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic

<400> SEQENCE: 43

agcagctgta ggcctgggat gtggaggcgt gtatgcggtg gcctcgctgg gaggcgtccg 60

tctggggaca tgctgctgct gaagaaacac acggaggaca tcagcagcgt ctacgagatc 120

cgcgagaggc tcggctcggg tgccttctcc gaggtggtgc tggcccagga gcggggctcc 180

gcacacctcg tggccctcaa gtgcatcccc aagaaggccc tccggggcaa ggaggccctg 240

gtggagaacg agatcgcagt gctccgtagg atcagtcacc ccaacatcgt cgctctggag 300

gatgtccacg agagcccttc ccacctctac ctggccatgg aactggtgac gggtggcgag 360

ctgtttgacc gcatcatgga gcgcggctcc tacacagaga aggatgccag ccatctggtg 420

ggtcaggtcc ttggcgccgt ctcctacctg cacagcctgg ggatcgtgca ccgggacctc 480

aagcccgaaa acctcctgta tgccacgccc tttgaggact cgaagatcat ggtctctgac 540

tttggactct ccaaaatcca ggctgggaac atgctaggca ccgcctgtgg gacccctgga 600

tatgtggccc cagagctctt ggagcagaaa ccctacggga aggccgtaga tgtgtgggcc 660

ctgggcgtca tctcctacat cctgctgtgt gggtaccccc ccttctacga cgagagcgac 720

cctgagctct tcagccagat cctgagggcc agctatgagt ttgactctcc tttctgggat 780

gacatctcag aatcagccaa agacttcatc cggcaccttc tggagcgaga cccccagaag 840

aggttcacct gccaacaggc cttgcggcac ctttggatct ctggggacac agccttcgac 900

agggacatct taggctctgt cagtgagcag atccggaaga actttgctcg gacacactgg 960

aagcgagcct tcaatgccac ctcgttcctg cgccacatcc ggaagctggg gcagatccca 1020

gagggcgagg gggcctctga gcagggcatg gcccgccaca gccactcagg cctccgtgct 1080

ggccagcccc ccaagtggtg atgcccaggc agatgccgag gccaagtgga ctgaccccca 1140

gatttccttc ccttggatgc tttcggtccc ctcccccaac ccctccccct ggggctggcc 1200

tctgctggat tttgagattt gagggtgtgg cgcatggcgc tggggttgga atggggcacc 1260

cccaagtctg tccccaggct ctgccctgcc tgggggcagt ggctcccctc ccctgttgcc 1320

tctcccgccc ctgccccccc cgccccgcca aaagccgagg gggtgctggc aggcgggcct 1380

caggggctgt ctttcctgca cggctgttgt gtgcttcgct gagtgtgggt ggtcctgctt 1440

gtgtcatggt catggccttc cagccccctc cagttttccc caaaccaata aagaaagata 1500

cagcaaaaaa aaaaaaaaaa aa 1522

<210> SEQ ID NO: 44

<211> LENGTH: 360

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic

<400> SEQENCE: 44

Met Trp Arg Arg Val Cys Gly Gly Leu Ala Gly Arg Arg Pro Ser Gly

1 5 10 15

Asp Met Leu Leu Leu Lys Lys His Thr Glu Asp Ile Ser Ser Val Tyr

20 25 30

Glu Ile Arg Glu Arg Leu Gly Ser Gly Ala Phe Ser Glu Val Val Leu

35 40 45

Ala Gln Glu Arg Gly Ser Ala His Leu Val Ala Leu Lys Cys Ile Pro

50 55 60

Lys Lys Ala Leu Arg Gly Lys Glu Ala Leu Val Glu Asn Glu Ile Ala

65 70 75 80

Val Leu Arg Arg Ile Ser His Pro Asn Ile Val Ala Leu Glu Asp Val

85 90 95

His Glu Ser Pro Ser His Leu Tyr Leu Ala Met Glu Leu Val Thr Gly

100 105 110

Gly Glu Leu Phe Asp Arg Ile Met Glu Arg Gly Ser Tyr Thr Glu Lys

115 120 125

Asp Ala Ser His Leu Val Gly Gln Val Leu Gly Ala Val Ser Tyr Leu

130 135 140

His Ser Leu Gly Ile Val His Arg Asp Leu Lys Pro Glu Asn Leu Leu

145 150 155 160

Tyr Ala Thr Pro Phe Glu Asp Ser Lys Ile Met Val Ser Asp Phe Gly

165 170 175

Leu Ser Lys Ile Gln Ala Gly Asn Met Leu Gly Thr Ala Cys Gly Thr

180 185 190

Pro Gly Tyr Val Ala Pro Glu Leu Leu Glu Gln Lys Pro Tyr Gly Lys

195 200 205

Ala Val Asp Val Trp Ala Leu Gly Val Ile Ser Tyr Ile Leu Leu Cys

210 215 220

Gly Tyr Pro Pro Phe Tyr Asp Glu Ser Asp Pro Glu Leu Phe Ser Gln

225 230 235 240

Ile Leu Arg Ala Ser Tyr Glu Phe Asp Ser Pro Phe Trp Asp Asp Ile

245 250 255

Ser Glu Ser Ala Lys Asp Phe Ile Arg His Leu Leu Glu Arg Asp Pro

260 265 270

Gln Lys Arg Phe Thr Cys Gln Gln Ala Leu Arg His Leu Trp Ile Ser

275 280 285

Gly Asp Thr Ala Phe Asp Arg Asp Ile Leu Gly Ser Val Ser Glu Gln

290 295 300

Ile Arg Lys Asn Phe Ala Arg Thr His Trp Lys Arg Ala Phe Asn Ala

305 310 315 320

Thr Ser Phe Leu Arg His Ile Arg Lys Leu Gly Gln Ile Pro Glu Gly

325 330 335

Glu Gly Ala Ser Glu Gln Gly Met Ala Arg His Ser His Ser Gly Leu

340 345 350

Arg Ala Gly Gln Pro Pro Lys Trp

355 360

<210> SEQ ID NO: 45

<211> LENGTH: 2242

<212> TYPE: DNA

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic

<400> SEQENCE: 45

agccggcgcg cggcggcggc aggaagtctg tgcccgagaa cagcagaaat aagagccagg 60

gagggaccgc ggccgcggcg gcggcggcga gagcgaaaga ggaaactgca gaggaggaag 120

ctgcgccgca gcccgagccg cccggcatcc ccgccgcctc tgcgcccgcg ccgcgccccc 180

ggcgccccct ccccagcgcg cccccggccg ctcctccgcg ccgcgctcgt cggccatggc 240

ccgggagaac ggcgagagca gctcctcctg gaaaaagcaa gctgaagaca tcaagaagat 300

cttcgagttc aaagagaccc tcggaaccgg ggccttttcc gaagtggttt tagctgaaga 360

gaaggcaact ggcaagctct ttgctgtgaa gtgtatccct aagaaggcgc tgaagggcaa 420

ggaaagcagc atagagaatg agatagccgt cctgagaaag attaagcatg aaaatattgt 480

tgccctggaa gacatttatg aaagcccaaa tcacctgtac ttggtcatgc agctggtgtc 540

cggtggagag ctgtttgacc ggatagtgga gaaggggttt tatacagaga aggatgccag 600

cactctgatc cgccaagtct tggacgccgt gtactatctc cacagaatgg gcatcgtcca 660

cagagacctc aagcccgaaa atctcttgta ctacagtcaa gatgaggagt ccaaaataat 720

gatcagtgac tttggattgt caaaaatgga gggcaaagga gatgtgatgt ccactgcctg 780

tggaactcca ggctatgtcg ctcctgaagt cctcgcccag aaaccttaca gcaaagccgt 840

tgactgctgg tccatcggag tgattgccta catcttgctc tgcggctacc ctccttttta 900

tgatgaaaat gactccaagc tctttgagca gatcctcaag gcggaatatg agtttgactc 960

tccctactgg gatgacatct ccgactctgc aaaagacttc attcggaacc tgatggagaa 1020

ggacccgaat aaaagataca cgtgtgagca ggcagctcgg cacccatgga tcgctggtga 1080

cacagccctc aacaaaaaca tccacgagtc cgtcagcgcc cagatccgga aaaactttgc 1140

caagagcaaa tggagacaag catttaatgc cacggccgtc gtcagacata tgagaaaact 1200

acacctcggc agcagcctgg acagttcaaa tgcaagtgtt tcgagcagcc tcagtttggc 1260

cagccaaaaa gactgtctgg caccttccac gctctgtagt ttcatttctt cttcgtcggg 1320

ggtctcagga gttggagccg agcggagacc caggcccacc actgtgacgg cagtgcactc 1380

tggaagcaag tgactggccc tggaggtggg gcccggggtc ggggctgggg aaggggagcc 1440

ccagggtcgc cagagccgcg agccactcca gcgagacccc accttgcatg gtgccccttc 1500

ctgcatagga ctggaagacc gaagtttttt tatggccata ttttctactg caattctgaa 1560

gtgttcattt ctcacaaact gtactgactc gaggggcgct gatttcatag gatctggtgc 1620

tgtatatacg aatcttgcaa agctctaact gaacggacct tcttattcct ctcccctaac 1680

accatcgttt ccactcttct cagtgtaggt aaccgtctat ggtgtgtttt ttcattaatg 1740

acaaaaaaaa aaaggtttca actggattat ttaaatattg gtaaatattg tgcattaggg 1800

tttgtttttc cttttaagaa gtatgtcctt tgtatctcta agttacatga cctatatctt 1860

ttcctcttta atagtagttt tatgttaacc tttaagagat ttgtttttcc tcaaaggaga 1920

atttaaaggt attttttaaa attctaataa gaggatcagc cgggtgcaat gactcatgcc 1980

tgtaatccca gcacgttggg aggccaagtc gggcggatca caaggtcagg agatcaaggc 2040

catcctggcc aacatggtga aaccccacgt ctactaaaaa tacaaaaaat tagccgggcg 2100

tggtggcaca cacctgtagt cccggctact cgggaggctg aggcaggaga attgcttgaa 2160

cccgggagac ggaggttgca gtgagctgag atcgtgccac tgcactccag cctgggtgac 2220

agagcaagac tctgtctcaa aa 2242

<210> SEQ ID NO: 46

<211> LENGTH: 385

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic

<400> SEQENCE: 46

Met Ala Arg Glu Asn Gly Glu Ser Ser Ser Ser Trp Lys Lys Gln Ala

1 5 10 15

Glu Asp Ile Lys Lys Ile Phe Glu Phe Lys Glu Thr Leu Gly Thr Gly

20 25 30

Ala Phe Ser Glu Val Val Leu Ala Glu Glu Lys Ala Thr Gly Lys Leu

35 40 45

Phe Ala Val Lys Cys Ile Pro Lys Lys Ala Leu Lys Gly Lys Glu Ser

50 55 60

Ser Ile Glu Asn Glu Ile Ala Val Leu Arg Lys Ile Lys His Glu Asn

65 70 75 80

Ile Val Ala Leu Glu Asp Ile Tyr Glu Ser Pro Asn His Leu Tyr Leu

85 90 95

Val Met Gln Leu Val Ser Gly Gly Glu Leu Phe Asp Arg Ile Val Glu

100 105 110

Lys Gly Phe Tyr Thr Glu Lys Asp Ala Ser Thr Leu Ile Arg Gln Val

115 120 125

Leu Asp Ala Val Tyr Tyr Leu His Arg Met Gly Ile Val His Arg Asp

130 135 140

Leu Lys Pro Glu Asn Leu Leu Tyr Tyr Ser Gln Asp Glu Glu Ser Lys

145 150 155 160

Ile Met Ile Ser Asp Phe Gly Leu Ser Lys Met Glu Gly Lys Gly Asp

165 170 175

Val Met Ser Thr Ala Cys Gly Thr Pro Gly Tyr Val Ala Pro Glu Val

180 185 190

Leu Ala Gln Lys Pro Tyr Ser Lys Ala Val Asp Cys Trp Ser Ile Gly

195 200 205

Val Ile Ala Tyr Ile Leu Leu Cys Gly Tyr Pro Pro Phe Tyr Asp Glu

210 215 220

Asn Asp Ser Lys Leu Phe Glu Gln Ile Leu Lys Ala Glu Tyr Glu Phe

225 230 235 240

Asp Ser Pro Tyr Trp Asp Asp Ile Ser Asp Ser Ala Lys Asp Phe Ile

245 250 255

Arg Asn Leu Met Glu Lys Asp Pro Asn Lys Arg Tyr Thr Cys Glu Gln

260 265 270

Ala Ala Arg His Pro Trp Ile Ala Gly Asp Thr Ala Leu Asn Lys Asn

275 280 285

Ile His Glu Ser Val Ser Ala Gln Ile Arg Lys Asn Phe Ala Lys Ser

290 295 300

Lys Trp Arg Gln Ala Phe Asn Ala Thr Ala Val Val Arg His Met Arg

305 310 315 320

Lys Leu His Leu Gly Ser Ser Leu Asp Ser Ser Asn Ala Ser Val Ser

325 330 335

Ser Ser Leu Ser Leu Ala Ser Gln Lys Asp Cys Leu Ala Pro Ser Thr

340 345 350

Leu Cys Ser Phe Ile Ser Ser Ser Ser Gly Val Ser Gly Val Gly Ala

355 360 365

Glu Arg Arg Pro Arg Pro Thr Thr Val Thr Ala Val His Ser Gly Ser

370 375 380

Lys

385

<210> SEQ ID NO: 47

<211> LENGTH: 2349

<212> TYPE: DNA

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic

<400> SEQENCE: 47

agggaggtgg ctgagcatca aataaatggt acagtccttg ctttaagaca tcagagagag 60

gagcgggcag ggagggcctg gctcacagca tttcaggaaa ctatcaggaa aagcaactct 120

tgagctaggg tttggatttg taggggcact tcccaacctt tcttacttaa ttggctttta 180

agtttacaca gctgtgtgta tatctaagtt tctgcctgtg tgagctacag tgttctaata 240

aaacacaggc aatttagtaa catgatgtaa acatacagaa ttgtttaaca agtaccagga 300

aaagacatcc agtaacagga aaggacaccc aaatctattt tggttacctt agtaaagcag 360

ggttgccaaa ctatttattg cccataagct aaatctgtca tgccacctgt tttttatggc 420

ctgctaagaa tggtttttac gtttttcttt tttctttttg tcaagatggg tcttgccatg 480

ttgtccaggc tggtctcaaa cttctaggct caagtgatcc tgccccctcg gcctcccaga 540

gtgctaagat tgtaatcacg cgtgtaggtg taagccacca cacctggcct ttcacatttt 600

tcaatggtta aataaaaacc aaaacagtaa tattttgtga cttatgaaaa tcatatgaaa 660

ttcagttttc agtgtctgta aataaagttt tattggaaca ctgccgcatg cattcattta 720

ctatttcctg tggctgctag gatggcaggg ttgagtagct gcattacaga gcctatggct 780

tgcaaagcct aaaatattta ctatctggcc ctttacaaag tttgctgacc ctgccttaaa 840

gtgccccaga taatctccac caggcctgat acatattttt tttggggggg gggggggaaa 900

tatgagaata tagaaaaata cgggactatg catcccccat tcagaattga ctattgctaa 960

cagtttgcca tttgcctcac agccatttat aagtactaaa aggaataaaa ctttacaaca 1020

ttccttatgc tccctgtccc gttctgtgct tttttccttc tttgtggcac actgtcatga 1080

atttaatgta tattcttctc tttgacttta aaaatcttgt atgtaagcat gtgtccatga 1140

acagtatcta ctgcatggga ttttaaggta cacacaaatt gtacatcatg ttgtattctg 1200

caacttgctg ttttactcaa cattatgttt ttgggatttc cttatgtcag tacagatcca 1260

gtgcacccct tttatctatt agatggtatt ccatcaaaca actataatga gtttcattta 1320

tccattcctt tgatgaacat ataggaagtt gttcccaggt ggtttttttt ttgtgttttt 1380

gttttgtttt gttttgtttt tgagatggag tcttgctctg tcacccaggc tggagtgcag 1440

tggcatgatc tcggctcact gcaacctctg cctcccgggt ttcaagcgat tctcctgcct 1500

cagcctcctg agtagttggg attacaggcg cgcgccacca tgcctggcta atttttgcat 1560

ttttttttta agtagagacg gggtttcacc atgctggtca ggctggactt gaactcctga 1620

cttcgtgatc tgcccacctt ggcctcccaa agtgctggga ttacaggcgt gagccactgt 1680

gcccagactt tttttttttt ttttgaaaca gtcttggtct gtcgtccagg ctggagggta 1740

gtggtgcgat ctctctgcct cccggttcaa gtggttctcg tgcttcagcc tcctgagtag 1800

ctgggattac gggcaccgcc accacaccgg gctaattttt gtatttttga tagagatggg 1860

gtttcaccat gctggccagg ctagtctcga acttctggcc tcaagtgatc tctccgcccg 1920

ggcctcccaa agtgctggga tcataggcgt gagccaccat gcccggcctc aggtttttgc 1980

catttccagc aaatgcatgc acgttgagta acatcagaag aggtggatgg ccgagcatgt 2040

tggctcatgc ctataatccc agcactttgg gaggcagagg caggaggatc acttgagccc 2100

aggagtttga gaccagcctg ggcaacatag ggagaactct gtctctacaa aaaatagaaa 2160

aaattagcca ggtgtggtgg tgtgtgcctg tagtcccagc tactcaggag gctgaggctg 2220

gaggatcacc tgagcctggg gaggtcgagg gtgcagcgag ccgtgatcgt gctactgcac 2280

tccagcctgg gcaacacaga gagaccctgt ctcaaaacaa acaaacaaac aaacaaacaa 2340

acaaacaaa 2349

<210> SEQ ID NO: 48

<211> LENGTH: 21

<212> TYPE: DNA

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic

<400> SEQENCE: 48

ggacatgttg ctggccaata a 21

<210> SEQ ID NO: 49

<211> LENGTH: 18

<212> TYPE: DNA

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic

<400> SEQENCE: 49

gggcccgaga ccagtgtt 18

<210> SEQ ID NO: 50

<211> LENGTH: 20

<212> TYPE: DNA

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic

<400> SEQENCE: 50

tccagaccag cccgacatag 20

<210> SEQ ID NO: 51

<211> LENGTH: 20

<212> TYPE: DNA

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic

<400> SEQENCE: 51

caggggtgca gcttgatttc 20

<210> SEQ ID NO: 52

<211> LENGTH: 21

<212> TYPE: DNA

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic

<400> SEQENCE: 52

tggccttatc ctgcctggta t 21

<210> SEQ ID NO: 53

<211> LENGTH: 21

<212> TYPE: DNA

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic

<400> SEQENCE: 53

aggagtcgat gctgatccca a 21

<210> SEQ ID NO: 54

<211> LENGTH: 20

<212> TYPE: DNA

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic

<400> SEQENCE: 54

ccatggcacc ttcagacttt 20

<210> SEQ ID NO: 55

<211> LENGTH: 20

<212> TYPE: DNA

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic

<400> SEQENCE: 55

actgggccat atgaggatca 20

<210> SEQ ID NO: 56

<211> LENGTH: 22

<212> TYPE: DNA

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic

<400> SEQENCE: 56

ctcagttcct ggagaaagat gg 22

<210> SEQ ID NO: 57

<211> LENGTH: 21

<212> TYPE: DNA

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic

<400> SEQENCE: 57

cccagtcaat tcatgtttgc c 21

<210> SEQ ID NO: 58

<211> LENGTH: 22

<212> TYPE: DNA

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic

<400> SEQENCE: 58

atggaatatg tgtctggagg tg 22

<210> SEQ ID NO: 59

<211> LENGTH: 21

<212> TYPE: DNA

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic

<400> SEQENCE: 59

tggtttcagg tctcgatgaa c 21

<210> SEQ ID NO: 60

<211> LENGTH: 20

<212> TYPE: DNA

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic

<400> SEQENCE: 60

gcacagtttg cacacctgaa 20

<210> SEQ ID NO: 61

<211> LENGTH: 20

<212> TYPE: DNA

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic

<400> SEQENCE: 61

gctttggatt taggccctgt 20

<210> SEQ ID NO: 62

<211> LENGTH: 20

<212> TYPE: DNA

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic

<400> SEQENCE: 62

aacaggaaag gacacccaaa 20

<210> SEQ ID NO: 63

<211> LENGTH: 21

<212> TYPE: DNA

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic

<400> SEQENCE: 63

aaaccattct tagcaggcca t 21

<210> SEQ ID NO: 64

<211> LENGTH: 31

<212> TYPE: DNA

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic

<400> SEQENCE: 64

cgctagcagg gaggtggctg agcatcaaat a 31

<210> SEQ ID NO: 65

<211> LENGTH: 32

<212> TYPE: DNA

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic

<400> SEQENCE: 65

caaagctttg agacagggtc tctctgtgtt gc 32

<210> SEQ ID NO: 66

<211> LENGTH: 31

<212> TYPE: DNA

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic

<400> SEQENCE: 66

cgctagcgaa ttgcaactgt gagaccaggc a 31

<210> SEQ ID NO: 67

<211> LENGTH: 32

<212> TYPE: DNA

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic

<400> SEQENCE: 67

caaagcttgt ggccttgggc aaatgacttg at 32

<210> SEQ ID NO: 68

<211> LENGTH: 31

<212> TYPE: DNA

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic

<400> SEQENCE: 68

cgctagcatc aagtcatttg cccaaggcca c 31

<210> SEQ ID NO: 69

<211> LENGTH: 32

<212> TYPE: DNA

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic

<400> SEQENCE: 69

caaagcttaa cactgtagct cacacaggca ga 32

<210> SEQ ID NO: 70

<211> LENGTH: 31

<212> TYPE: DNA

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic

<400> SEQENCE: 70

cgctagcatc aagtcatttg cccaaggcca c 31

<210> SEQ ID NO: 71

<211> LENGTH: 32

<212> TYPE: DNA

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic

<400> SEQENCE: 71

caaagcttta tttgatgctc agccacctcc ct 32

<210> SEQ ID NO: 72

<211> LENGTH: 31

<212> TYPE: DNA

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic

<400> SEQENCE: 72

cgctagcagg gaggtggctg agcatcaaat a 31

<210> SEQ ID NO: 73

<211> LENGTH: 32

<212> TYPE: DNA

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic

<400> SEQENCE: 73

caaagcttaa atgtgaaagg ccaggtgtgg tg 32

<210> SEQ ID NO: 74

<211> LENGTH: 31

<212> TYPE: DNA

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic

<400> SEQENCE: 74

cgctagctgc ctgtgtgagc tacagtgttc t 31

<210> SEQ ID NO: 75

<211> LENGTH: 32

<212> TYPE: DNA

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic

<400> SEQENCE: 75

caaagcttaa atgtgaaagg ccaggtgtgg tg 32

<210> SEQ ID NO: 76

<211> LENGTH: 31

<212> TYPE: DNA

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic

<400> SEQENCE: 76

cgctagcagg gaggtggctg agcatcaaat a 31

<210> SEQ ID NO: 77

<211> LENGTH: 32

<212> TYPE: DNA

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic

<400> SEQENCE: 77

caaagcttaa cactgtagct cacacaggca ga 32

<210> SEQ ID NO: 78

<211> LENGTH: 31

<212> TYPE: DNA

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic

<400> SEQENCE: 78

cgctagccac cacacctggc ctttcacatt t 31

<210> SEQ ID NO: 79

<211> LENGTH: 32

<212> TYPE: DNA

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic

<400> SEQENCE: 79

caaagcttgc actttaaggc agggtcagca aa 32

<210> SEQ ID NO: 80

<211> LENGTH: 31

<212> TYPE: DNA

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic

<400> SEQENCE: 80

cgctagcgtt tcaagcgatt ctcctgcctc a 31

<210> SEQ ID NO: 81

<211> LENGTH: 32

<212> TYPE: DNA

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic

<400> SEQENCE: 81

caaagctttc acgcctgtaa tcccagcact tt 32

<210> SEQ ID NO: 82

<211> LENGTH: 31

<212> TYPE: DNA

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic

<400> SEQENCE: 82

cgctagcagg gaggtggctg agcatcaaat a 31

<210> SEQ ID NO: 83

<211> LENGTH: 32

<212> TYPE: DNA

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic

<400> SEQENCE: 83

caaagcttta cacgggtgat tacaatctta gc 32

<210> SEQ ID NO: 84

<211> LENGTH: 31

<212> TYPE: DNA

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic

<400> SEQENCE: 84

cgctagcagg gaggtggctg agcatcaaat a 31

<210> SEQ ID NO: 85

<211> LENGTH: 32

<212> TYPE: DNA

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic

<400> SEQENCE: 85

caaagctttg gacaacatgg caagacccat ct 32

<210> SEQ ID NO: 86

<211> LENGTH: 31

<212> TYPE: DNA

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic

<400> SEQENCE: 86

cgctagcagg gaggtggctg agcatcaaat a 31

<210> SEQ ID NO: 87

<211> LENGTH: 32

<212> TYPE: DNA

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic

<400> SEQENCE: 87

caaagcttct ggatctcttt tcctggtact tg 32

<210> SEQ ID NO: 88

<211> LENGTH: 31

<212> TYPE: DNA

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic

<400> SEQENCE: 88

cgctagcagg gaggtggctg agcatcaaat a 31

<210> SEQ ID NO: 89

<211> LENGTH: 32

<212> TYPE: DNA

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic

<400> SEQENCE: 89

caaagcttac actgtagctc acacaggcag aa 32

<210> SEQ ID NO: 90

<211> LENGTH: 31

<212> TYPE: DNA

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic

<400> SEQENCE: 90

cgctagcagg gaggtggctg agcatcaaat a 31

<210> SEQ ID NO: 91

<211> LENGTH: 32

<212> TYPE: DNA

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic

<400> SEQENCE: 91

caaagcttta caaatccaaa ccctagctca ag 32

<210> SEQ ID NO: 92

<211> LENGTH: 31

<212> TYPE: DNA

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic

<400> SEQENCE: 92

cgctagcagg gaggtggctg agcatcaaat a 31

<210> SEQ ID NO: 93

<211> LENGTH: 32

<212> TYPE: DNA

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic

<400> SEQENCE: 93

caaagctttg ctgtgagcca ggccctccct gc 32

<210> SEQ ID NO: 94

<211> LENGTH: 31

<212> TYPE: DNA

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic

<400> SEQENCE: 94

cgctagcagg gaggtggctg agcatcaaat a 31

<210> SEQ ID NO: 95

<211> LENGTH: 32

<212> TYPE: DNA

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic

<400> SEQENCE: 95

caaagcttct gcccgctcct ctctctgatg tc 32

<210> SEQ ID NO: 96

<211> LENGTH: 25

<212> TYPE: DNA

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic

<400> SEQENCE: 96

catacagaat tgtttaacaa gtacc 25

<210> SEQ ID NO: 97

<211> LENGTH: 29

<212> TYPE: DNA

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic

<400> SEQENCE: 97

taaattgcct gtgttttatt agaacactg 29

<210> SEQ ID NO: 98

<211> LENGTH: 24

<212> TYPE: DNA

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic

<400> SEQENCE: 98

acctgtaatc ccagcacttt cgga 24

<210> SEQ ID NO: 99

<211> LENGTH: 24

<212> TYPE: DNA

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic

<400> SEQENCE: 99

cgatctcgga tcactgcaac ctct 24

<210> SEQ ID NO: 100

<211> LENGTH: 22

<212> TYPE: DNA

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic

<400> SEQENCE: 100

tgagccgagc cgagccgagc tg 22

<210> SEQ ID NO: 101

<211> LENGTH: 23

<212> TYPE: DNA

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic

<400> SEQENCE: 101

tcacagggct tctggctttc gct 23

<210> SEQ ID NO: 102

<211> LENGTH: 24

<212> TYPE: DNA

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic

<400> SEQENCE: 102

agctgaggac ttgaaggacc tgat 24

<210> SEQ ID NO: 103

<211> LENGTH: 23

<212> TYPE: DNA

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic

<400> SEQENCE: 103

aggttgtctt cgctgccttg ctt 23

<210> SEQ ID NO: 104

<211> LENGTH: 24

<212> TYPE: DNA

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic

<400> SEQENCE: 104

acctgggctg gctatgtgta tgaa 24

<210> SEQ ID NO: 105

<211> LENGTH: 25

<212> TYPE: RNA

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic

<400> SEQENCE: 105

ggaccaucug uacauggugu ucgaa 25

<210> SEQ ID NO: 106

<211> LENGTH: 25

<212> TYPE: RNA

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic

<400> SEQENCE: 106

gcugacuuug gugugagcaa ugaau 25

<210> SEQ ID NO: 107

<211> LENGTH: 25

<212> TYPE: RNA

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic

<400> SEQENCE: 107

caccugggca uggaguccuu cauug 25

<210> SEQ ID NO: 108

<211> LENGTH: 25

<212> TYPE: RNA

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic

<400> SEQENCE: 108

cagaugucuu cugccuguua uaacu 25

<210> SEQ ID NO: 109

<211> LENGTH: 25

<212> TYPE: RNA

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic

<400> SEQENCE: 109

cccauccuga aagaguacca uucuu 25

<210> SEQ ID NO: 110

<211> LENGTH: 25

<212> TYPE: RNA

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic

<400> SEQENCE: 110

cccucaauau uuaaauccuu cugug 25

<210> SEQ ID NO: 111

<211> LENGTH: 25

<212> TYPE: RNA

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic

<400> SEQENCE: 111

accaugauug augaugaagc cuuaa 25

<210> SEQ ID NO: 112

<211> LENGTH: 25

<212> TYPE: RNA

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic

<400> SEQENCE: 112

gauggugaau uucugagaac uaguu 25

<210> SEQ ID NO: 113

<211> LENGTH: 25

<212> TYPE: RNA

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic

<400> SEQENCE: 113

ccguaugaca uuauggcuga aguuu 25

<210> SEQ ID NO: 114

<211> LENGTH: 25

<212> TYPE: DNA

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic

<400> SEQENCE: 114

ggagatacag ctctagataa gaata 25

<210> SEQ ID NO: 115

<211> LENGTH: 25

<212> TYPE: DNA

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic

<400> SEQENCE: 115

ccataggtgt catcgcctac atctt 25

<210> SEQ ID NO: 116

<211> LENGTH: 15

<212> TYPE: DNA

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic

<400> SEQENCE: 116

gtaacatgat gtaaa 15

<210> SEQ ID NO: 117

<211> LENGTH: 15

<212> TYPE: DNA

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic

<220> FEATURE:

<221> NAME/KEY: misc_feature

<222> LOCATION: (7)..(9)

<223> OTHER INFORMATION: n is a, c, g, or t

<400> SEQENCE: 117

agaacannnt gttct 15

<210> SEQ ID NO: 118

<211> LENGTH: 19

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic

<400> SEQENCE: 118

Lys Lys Lys Lys Glu His Gln Val Leu Met Lys Thr Val Cys Gly Thr

1 5 10 15

Pro Gly Tyr

<210> SEQ ID NO: 119

<211> LENGTH: 23

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic

<400> SEQENCE: 119

Ala Lys Pro Lys Gly Asn Lys Asp Tyr His Leu Gln Thr Cys Cys Gly

1 5 10 15

Ser Leu Ala Tyr Arg Arg Arg

20

Read more
PatSnap Solutions

Great research starts with great data.

Use the most comprehensive innovation intelligence platform to maximise ROI on research.

Learn More

Patent Valuation

$

Reveal the value <>

24.16/100 Score

Market Attractiveness

It shows from an IP point of view how many competitors are active and innovations are made in the different technical fields of the company. On a company level, the market attractiveness is often also an indicator of how diversified a company is. Here we look into the commercial relevance of the market.

49.0/100 Score

Market Coverage

It shows the sizes of the market that is covered with the IP and in how many countries the IP guarantees protection. It reflects a market size that is potentially addressable with the invented technology/formulation with a legal protection which also includes a freedom to operate. Here we look into the size of the impacted market.

72.58/100 Score

Technology Quality

It shows the degree of innovation that can be derived from a company’s IP. Here we look into ease of detection, ability to design around and significance of the patented feature to the product/service.

64.0/100 Score

Assignee Score

It takes the R&D behavior of the company itself into account that results in IP. During the invention phase, larger companies are considered to assign a higher R&D budget on a certain technology field, these companies have a better influence on their market, on what is marketable and what might lead to a standard.

23.96/100 Score

Legal Score

It shows the legal strength of IP in terms of its degree of protecting effect. Here we look into claim scope, claim breadth, claim quality, stability and priority.

Citation

Patents Cited in This Cited by
Title Current Assignee Application Date Publication Date
Camkk(BETA) as a target for treating obesity DUKE UNIVERSITY 04 October 2007 29 April 2010
Process of preparing derivatives of 1.4.5.8-naphthalene-tetracarboxylic acid FARBWERKE HOECHST AKTIENGESELLSCHAFT VORMALS MEISTER LUCIUS & BRUNING 25 March 1955 20 May 1958
Molecular signatures of commonly fatal carcinomas IRM LLC 09 March 2006 21 September 2006
Modulators of angiogenesis RIGEL PHARMACEUTICALS, INCORPORATED 13 January 2005 22 September 2005
新規なCaMKK阻害剤 大日本住友製薬株式会社 25 December 2001 15 January 2003
See full citation <>

More like this

Title Current Assignee Application Date Publication Date
Methods of treating cancer harboring hemizygous loss of TP53 BOARD OF REGENTS, THE UNIVERSITY OF TEXAS SYSTEM 03 March 2016 09 September 2016
Human monoclonal antibodies against CD20 GENMAB A/S 17 October 2003 27 August 2014
Method of diagnosing bladder cancer ONCOTHERAPY SCIENCE, INC. 09 February 2006 07 January 2009
High affinity human antibodies and human antibodies against human antigens GENPHARM INTERNATIONAL, INC. 10 October 1996 01 August 2006
Detection of genomic amplification and deletion in cancer NOVARTIS AG,NOVARTIS PHARMA GMBH,DRESSMAN, MARLENE, MICHELLE,MALINOWSKI, RACHEL, HELENE,POLYMEROPOULOS, MIHAEL, HRISTOS 12 November 2004 26 May 2005
Transgenic non-human animals for producing chimeric antibodies GENPHARM INTERNATIONAL 26 September 2008 23 October 2012
Kinases and uses thereof MILLENNIUM PHARMACEUTICALS, INC. 07 May 2008 02 February 2010
Tumour suppressor genes PROCURE THERAPEUTICS LIMITED,SHARRAD, MICHAEL 02 December 2005 21 September 2006
CACNA1E in cancer diagnosis detection and treatment NOVARTIS VACCINES AND DIAGNOSTICS, INC.,SAGRES DISCOVERY, INC. 07 April 2006 27 May 2009
Antibodies to MAdCAM PFIZER INC.,AMGEN FREMONT INC. 10 July 2006 19 July 2007
액티빈 수용체 유사 키나제-1에 대한 인간 모노클로날 항체 암젠 프레몬트 인코포레이티드,화이자 인크. 06 September 2006 26 April 2013
Transgenic animals for producing specific isotypes of human antibodies via non-cognate switch regions ABGENIX, INC. 30 November 2001 23 May 2006
Compositions, kits and methods for identification, assessment, prevention and therapy of cervical cancer MILLENNIUM PHARMACEUTICALS, INC. 20 August 2003 20 April 2011
Antibodies to insulin-like growth factor I receptor PFIZER INC.,AMGEN FREMONT INC. 19 December 2013 12 January 2016
Prognostic and predictive gene signature for non-small cell lung cancer and adjuvant chemotherapy UNIVERSITY HEALTH NETWORK 14 May 2009 28 January 2015
94 human secreted proteins HUMAN GENOME SCIENCES, INC. 16 March 2004 29 July 2004
Transgenic animals producing monovalent human antibodies and antibodies obtainable from these animals GENMAB A/S,SCHUURMAN, JANINE,VINK, TOM,VAN DE WINKEL, JAN,LABRIJN, ARAN FRANK 30 May 2008 04 December 2008
Animal models and therapeutic molecules KYMAB LIMITED 06 November 2015 29 November 2016
Transgenic non-human animals for producing heterologous antibodies GENPHARM INTERNATIONAL INC. 22 July 1993 29 September 1998
Mutations in the BCR-Abl-tyrosine kinase associated with resistance to STI-571 THE REGENTS OF THE UNIVERSITY OF CALIFORNIA 14 June 2002 03 June 2015
See all similar patents <>

More Patents & Intellectual Property

PatSnap Solutions

PatSnap solutions are used by R&D teams, legal and IP professionals, those in business intelligence and strategic planning roles and by research staff at academic institutions globally.

PatSnap Solutions
Search & Analyze
The widest range of IP search tools makes getting the right answers and asking the right questions easier than ever. One click analysis extracts meaningful information on competitors and technology trends from IP data.
Business Intelligence
Gain powerful insights into future technology changes, market shifts and competitor strategies.
Workflow
Manage IP-related processes across multiple teams and departments with integrated collaboration and workflow tools.
Contact Sales
Clsoe
US9999620 CaMKK-β target 1 US9999620 CaMKK-β target 2 US9999620 CaMKK-β target 3