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標題: Cdk5蛋白藉由干擾cyclin D1調控雄性激素受體活性
Cdk5 Interferes Cyclin D1-Dependent Activation of Androgen Receptor
作者: 林俐伶
Lin, Li-Ling
關鍵字: Cdk5;Cdk5;cyclin D1;Androgen Receptor;cyclin D1;雄性激素受體
出版社: 生命科學系所
引用: 1. Parkin, D. M., Bray, F., Ferlay, J., and Pisani, P. Global cancer statistics, 2002. CA Cancer J Clin, 55: 74-108, 2005. 2. Boyle, P. and Ferlay, J. Cancer incidence and mortality in Europe, 2004. Ann Oncol, 16: 481-488, 2005. 3. Ferlay, J., Bray, F., Pisani, P., and Parkin, D. M. Cancer incidence, mortality and prevalence worldwide, version1.0. IARC Cancer Base No. 5 book. Lyon: IARC Press, 2001. 4. Hsing, A. W., Tsao, L., and Devesa, S. S. International trends and patterns of prostate cancer incidence and mortality. Int J Cancer, 85: 60-67, 2000. 5. Suzuki, H., Ueda, T., Ichikawa, T., and Ito, H. Androgen receptor involvement in the progression of prostate cancer. Endocr Relat Cancer, 10: 209-216, 2003. 6. Culig, Z. Role of the androgen receptor axis in prostate cancer. Urology, 62: 21-26, 2003. 7. Culig, Z. and Bartsch, G. Androgen axis in prostate cancer. J Cell Biochem, 99: 373-381, 2006. 8. Henderson, B. E., Ross, R. K., Pike, M. C., and Casagrande, J. T. Endogenous hormones as a major factor in human cancer. Cancer Res, 42: 3232-3239, 1982. 9. Glantz, G. M. Cirrhosis and Carcinoma of the Prostate Gland. J Urol, 91: 291-293, 1964. 10. Huggins, C. and Hodges, C. V. Studies on prostatic cancer. I. The effect of castration, of estrogen and androgen injection on serum phosphatases in metastatic carcinoma of the prostate. CA Cancer J Clin, 22: 232-240, 1972. 11. Marumo, K., Baba, S., and Murai, M. Erectile function and nocturnal penile tumescence in patients with prostate cancer undergoing luteinizing hormone-releasing hormone agonist therapy. Int J Urol, 6: 19-23, 1999. 12. Ornstein, D. K., Oh, J., Herschman, J. D., and Andriole, G. L. Evaluation and management of the man who has failed primary curative therapy for prostate cancer. Urol Clin North Am, 25: 591-601, 1998. 13. Lilja, H. A kallikrein-like serine protease in prostatic fluid cleaves the predominant seminal vesicle protein. J Clin Invest, 76: 1899-1903, 1985. 14. van der Cruijsen-Koeter, I. W., Vis, A. N., Roobol, M. J., Wildhagen, M. F., de Koning, H. J., van der Kwast, T. H., and Schroder, F. H. Comparison of screen detected and clinically diagnosed prostate cancer in the European randomized study of screening for prostate cancer, section rotterdam. J Urol, 174: 121-125, 2005. 15. Damber, J. E. and Aus, G. Prostate cancer. Lancet, 371: 1710-1721, 2008. 16. Brown, J. R., Nigh, E., Lee, R. J., Ye, H., Thompson, M. A., Saudou, F., Pestell, R. G., and Greenberg, M. E. Fos family members induce cell cycle entry by activating cyclin D1. Mol Cell Biol, 18: 5609-5619, 1998. 17. Herber, B., Truss, M., Beato, M., and Muller, R. Inducible regulatory elements in the human cyclin D1 promoter. Oncogene, 9: 2105-2107, 1994. 18. Knudsen, K. E., Diehl, J. A., Haiman, C. A., and Knudsen, E. S. Cyclin D1: polymorphism, aberrant splicing and cancer risk. Oncogene, 25: 1620-1628, 2006. 19. Bosch, F., Jares, P., Campo, E., Lopez-Guillermo, A., Piris, M. A., Villamor, N., Tassies, D., Jaffe, E. S., Montserrat, E., Rozman, C., and et al. PRAD-1/cyclin D1 gene overexpression in chronic lymphoproliferative disorders: a highly specific marker of mantle cell lymphoma. Blood, 84: 2726-2732, 1994. 20. Zwijsen, R. M., Buckle, R. S., Hijmans, E. M., Loomans, C. J., and Bernards, R. Ligand-independent recruitment of steroid receptor coactivators to estrogen receptor by cyclin D1. Genes Dev, 12: 3488-3498, 1998. 21. Knudsen, K. E., Cavenee, W. K., and Arden, K. C. D-type cyclins complex with the androgen receptor and inhibit its transcriptional transactivation ability. Cancer Res, 59: 2297-2301, 1999. 22. Martinez, E. D. and Danielsen, M. Loss of androgen receptor transcriptional activity at the G(1)/S transition. J Biol Chem, 277: 29719-29729, 2002. 23. Petre-Draviam, C. E., Cook, S. L., Burd, C. J., Marshall, T. W., Wetherill, Y. B., and Knudsen, K. E. Specificity of cyclin D1 for androgen receptor regulation. Cancer Res, 63: 4903-4913, 2003. 24. Petre, C. E., Wetherill, Y. B., Danielsen, M., and Knudsen, K. E. Cyclin D1: mechanism and consequence of androgen receptor co-repressor activity. J Biol Chem, 277: 2207-2215, 2002. 25. Burd, C. J., Petre, C. E., Moghadam, H., Wilson, E. M., and Knudsen, K. E. Cyclin D1 binding to the androgen receptor (AR) NH2-terminal domain inhibits activation function 2 association and reveals dual roles for AR corepression. Mol Endocrinol, 19: 607-620, 2005. 26. Balk, S. P. Androgen receptor as a target in androgen-independent prostate cancer. Urology, 60: 132-138; discussion 138-139, 2002. 27. Culig, Z., Hobisch, A., Cronauer, M. V., Radmayr, C., Trapman, J., Hittmair, A., Bartsch, G., and Klocker, H. Androgen receptor activation in prostatic tumor cell lines by insulin-like growth factor-I, keratinocyte growth factor, and epidermal growth factor. Cancer Res, 54: 5474-5478, 1994. 28. Hobisch, A., Eder, I. E., Putz, T., Horninger, W., Bartsch, G., Klocker, H., and Culig, Z. Interleukin-6 regulates prostate-specific protein expression in prostate carcinoma cells by activation of the androgen receptor. Cancer Res, 58: 4640-4645, 1998. 29. Russell, P. J., Bennett, S., and Stricker, P. Growth factor involvement in progression of prostate cancer. Clin Chem, 44: 705-723, 1998. 30. Drachenberg, D. E., Elgamal, A. A., Rowbotham, R., Peterson, M., and Murphy, G. P. Circulating levels of interleukin-6 in patients with hormone refractory prostate cancer. Prostate, 41: 127-133, 1999. 31. Giri, D., Ozen, M., and Ittmann, M. Interleukin-6 is an autocrine growth factor in human prostate cancer. Am J Pathol, 159: 2159-2165, 2001. 32. Ueda, T., Bruchovsky, N., and Sadar, M. D. Activation of the androgen receptor N-terminal domain by interleukin-6 via MAPK and STAT3 signal transduction pathways. J Biol Chem, 277: 7076-7085, 2002. 33. Lim, J. T., Mansukhani, M., and Weinstein, I. B. Cyclin-dependent kinase 6 associates with the androgen receptor and enhances its transcriptional activity in prostate cancer cells. Proc Natl Acad Sci USA, 102: 5156-5161, 2005. 34. Burd, C. J., Petre, C. E., Morey, L. M., Wang, Y., Revelo, M. P., Haiman, C. A., Lu, S., Fenoglio-Preiser, C. M., Li, J., Knudsen, E. S., Wong, J., and Knudsen, K. E. Cyclin D1b variant influences prostate cancer growth through aberrant androgen receptor regulation. Proc Natl Acad Sci USA, 103: 2190-2195, 2006. 35. Knudsen, K. E. The cyclin D1b splice variant: an old oncogene learns new tricks. Cell Div, 1: 15, 2006. 36. Hellmich, M. R., Pant, H. C., Wada, E., and Battey, J. F. Neuronal cdc2-like kinase: a cdc2-related protein kinase with predominantly neuronal expression. Proc Natl Acad Sci USA, 89: 10867-10871, 1992. 37. Lew, J., Beaudette, K., Litwin, C. M., and Wang, J. H. Purification and characterization of a novel proline-directed protein kinase from bovine brain. J Biol Chem, 267: 13383-13390, 1992. 38. Morgan, D. O. Principles of CDK regulation. Nature, 374: 131-134, 1995. 39. Xiong, Y., Zhang, H., and Beach, D. D type cyclins associate with multiple protein kinases and the DNA replication and repair factor PCNA. Cell, 71: 505-514, 1992. 40. Miyajima, M., Nornes, H. O., and Neuman, T. Cyclin E is expressed in neurons and forms complexes with cdk5. Neuroreport, 6: 1130-1132, 1995. 41. Lew, J., Huang, Q. Q., Qi, Z., Winkfein, R. J., Aebersold, R., Hunt, T., and Wang, J. H. A brain-specific activator of cyclin-dependent kinase 5. Nature, 371: 423-426, 1994. 42. Tang, D., Yeung, J., Lee, K. Y., Matsushita, M., Matsui, H., Tomizawa, K., Hatase, O., and Wang, J. H. An isoform of the neuronal cyclin-dependent kinase 5 (Cdk5) activator. J Biol Chem, 270: 26897-26903, 1995. 43. Weishaupt, J. H., Neusch, C., and Bahr, M. Cyclin-dependent kinase 5 (CDK5) and neuronal cell death. Cell Tissue Res, 312: 1-8, 2003. 44. Dhavan, R. and Tsai, L. H. A decade of CDK5. Nat Rev Mol Cell Biol, 2: 749-759, 2001. 45. Dhariwala, F. A. and Rajadhyaksha, M. S. An unusual member of the Cdk family: Cdk5. Cell Mol Neurobiol, 28: 351-369, 2008. 46. Maccioni, R. B., Otth, C., Concha, II, and Munoz, J. P. The protein kinase Cdk5. Structural aspects, roles in neurogenesis and involvement in Alzheimer''s pathology. Eur J Biochem, 268: 1518-1527, 2001. 47. Lee, M. S. and Tsai, L. H. Cdk5: one of the links between senile plaques and neurofibrillary tangles? J Alzheimers Dis, 5: 127-137, 2003. 48. Neystat, M., Rzhetskaya, M., Oo, T. F., Kholodilov, N., Yarygina, O., Wilson, A., El-Khodor, B. F., and Burke, R. E. Expression of cyclin-dependent kinase 5 and its activator p35 in models of induced apoptotic death in neurons of the substantia nigra in vivo. J Neurochem, 77: 1611-1625, 2001. 49. Hamdane, M., Sambo, A. V., Delobel, P., Begard, S., Violleau, A., Delacourte, A., Bertrand, P., Benavides, J., and Buee, L. Mitotic-like tau phosphorylation by p25-Cdk5 kinase complex. J Biol Chem, 278: 34026-34034, 2003. 50. Nguyen, M. D., Lariviere, R. C., and Julien, J. P. Deregulation of Cdk5 in a mouse model of ALS: toxicity alleviated by perikaryal neurofilament inclusions. Neuron, 30: 135-147, 2001. 51. Luo, S., Vacher, C., Davies, J. E., and Rubinsztein, D. C. Cdk5 phosphorylation of huntingtin reduces its cleavage by caspases: implications for mutant huntingtin toxicity. J Cell Biol, 169: 647-656, 2005. 52. Brown, N. R., Noble, M. E., Endicott, J. A., Garman, E. F., Wakatsuki, S., Mitchell, E., Rasmussen, B., Hunt, T., and Johnson, L. N. The crystal structure of cyclin A. Structure, 3: 1235-1247, 1995. 53. Tang, D., Chun, A. C., Zhang, M., and Wang, J. H. Cyclin-dependent kinase 5 (Cdk5) activation domain of neuronal Cdk5 activator. Evidence of the existence of cyclin fold in neuronal Cdk5a activator. J Biol Chem, 272: 12318-12327, 1997. 54. Patrick, G. N., Zhou, P., Kwon, Y. T., Howley, P. M., and Tsai, L. H. p35, the neuronal-specific activator of cyclin-dependent kinase 5 (Cdk5) is degraded by the ubiquitin-proteasome pathway. J Biol Chem, 273: 24057-24064, 1998. 55. Cruz, J. C. and Tsai, L. H. Cdk5 deregulation in the pathogenesis of Alzheimer''s disease. Trends Mol Med, 10: 452-458, 2004. 56. Patrick, G. N., Zukerberg, L., Nikolic, M., de la Monte, S., Dikkes, P., and Tsai, L. H. Conversion of p35 to p25 deregulates Cdk5 activity and promotes neurodegeneration. Nature, 402: 615-622, 1999. 57. Musa, F. R., Tokuda, M., Kuwata, Y., Ogawa, T., Tomizawa, K., Konishi, R., Takenaka, I., and Hatase, O. Expression of cyclin-dependent kinase 5 and associated cyclins in Leydig and Sertoli cells of the testis. J Androl, 19: 657-666, 1998. 58. Musa, F. R., Takenaka, I., Konishi, R., and Tokuda, M. Effects of luteinizing hormone, follicle-stimulating hormone, and epidermal growth factor on expression and kinase activity of cyclin-dependent kinase 5 in Leydig TM3 and Sertoli TM4 cell lines. J Androl, 21: 392-402, 2000. 59. Lin, H., Juang, J. L., and Wang, P. S. Involvement of Cdk5/p25 in digoxin-triggered prostate cancer cell apoptosis. J Biol Chem, 279: 29302-29307, 2004. 60. Strock, C. J., Park, J. I., Nakakura, E. K., Bova, G. S., Isaacs, J. T., Ball, D. W., and Nelkin, B. D. Cyclin-dependent kinase 5 activity controls cell motility and metastatic potential of prostate cancer cells. Cancer Res, 66: 7509-7515, 2006. 61. Yamamoto, A., Hashimoto, Y., Kohri, K., Ogata, E., Kato, S., Ikeda, K., and Nakanishi, M. Cyclin E as a coactivator of the androgen receptor. J Cell Biol, 150: 873-880, 2000. 62. Olshavsky, N. A., Groh, E. M., Comstock, C. E., Morey, L. M., Wang, Y., Revelo, M. P., Burd, C., Meller, J., and Knudsen, K. E. Cyclin D3 action in androgen receptor regulation and prostate cancer. Oncogene, 27: 3111-3121, 2008. 63. Zong, H., Chi, Y., Wang, Y., Yang, Y., Zhang, L., Chen, H., Jiang, J., Li, Z., Hong, Y., Wang, H., Yun, X., and Gu, J. Cyclin D3/CDK11p58 complex is involved in the repression of androgen receptor. Mol Cell Biol, 27: 7125-7142, 2007. 64. Chen, S., Xu, Y., Yuan, X., Bubley, G. J., and Balk, S. P. Androgen receptor phosphorylation and stabilization in prostate cancer by cyclin-dependent kinase 1. Proc Natl Acad Sci USA, 103: 15969-15974, 2006. 65. Lee, M. H., Nikolic, M., Baptista, C. A., Lai, E., Tsai, L. H., and Massague, J. The brain-specific activator p35 allows Cdk5 to escape inhibition by p27Kip1 in neurons. Proc Natl Acad Sci USA, 93: 3259-3263, 1996. 66. Lin, H., Chen, M. C., Chiu, C. Y., Song, Y. M., and Lin, S. Y. Cdk5 regulates STAT3 activation and cell proliferation in medullary thyroid carcinoma cells. J Biol Chem, 282: 2776-2784, 2007. 67. Gioeli, D., Ficarro, S. B., Kwiek, J. J., Aaronson, D., Hancock, M., Catling, A. D., White, F. M., Christian, R. E., Settlage, R. E., Shabanowitz, J., Hunt, D. F., and Weber, M. J. Androgen receptor phosphorylation. Regulation and identification of the phosphorylation sites. J Biol Chem, 277: 29304-29314, 2002. 68. Fu, A. K., Fu, W. Y., Ng, A. K., Chien, W. W., Ng, Y. P., Wang, J. H., and Ip, N. Y. Cyclin-dependent kinase 5 phosphorylates signal transducer and activator of transcription 3 and regulates its transcriptional activity. Proc Natl Acad Sci USA, 101: 6728-6733, 2004.
雄性激素受體 (AR) 對於攝護腺癌的生長及發育相當重要,許多蛋白質激酶會藉由磷酸化AR絲氨酸或蘇氨酸而調控AR的活性。然而研究指出,cyclin D1會直接和AR結合抑制AR的轉錄活性,並抑制雄性激素所調控的攝護腺癌細胞增生。本研究欲探討的Cdk5蛋白屬於cyclin-dependent kinase (Cdk) 家族的成員之ㄧ,是ㄧ種絲氨酸-蘇氨酸蛋白激酶,其專一的活化蛋白為p35。有異於其他Cdk家族成員,截至目前的研究尚未發現Cdk5具有直接調控細胞週期的能力。本實驗室的研究首先發現Cdk5和AR有交互作用的情況,並有正向調控AR的能力,除此之外,和cyclin D1結構相似的p35蛋白也和AR有交互作用。有趣的是,利用質體DNA轉染的方式表現Cdk5及p35蛋白會干擾cyclin D1和AR的交互作用,進ㄧ步的研究發現,cyclin D1會抑制AR下游調控蛋白PSA的表現,然而Cdk5和AR間的交互作用使細胞內PSA蛋白的表現以及PSA蛋白的分泌有顯著增加的情形,若利用RNA干擾技術降低Cdk5的表現,則發現PSA蛋白的表現及分泌受到抑制。因此推測Cdk5會藉由干擾cyclin D1和AR間的交互作用而調控AR的活性。綜合上述的研究,Cdk5對於AR活性的調控在攝護腺癌細胞中扮演重要的角色,而Cdk5及AR相關的基礎研究可能對未來攝護腺癌的治療開啟ㄧ個新方向。

The androgen receptor (AR) is important for the development of prostate cancer. Several protein kinases have been shown to regulate AR transactivation by phosphorylating serine or threonine residues in AR. On the other hand, cyclin D1 harbors a distinct anti-mitogenic function and inhibits androgen-dependent proliferation in prostatic adenocarcinoma. In which, cyclin D1 was reported to directly interact with AR and negatively regulate AR transactivation. Cdk5 protein, the main focus in this study, is a member of serine/threonine cyclin-dependent kinase (CDK) family and its regulator is p35 protein. In contrast to other members of the CDK family, Cdk5 is not directly involved in cell cycle modulation. Our previous results indicated that Cdk5 could associate with AR and performed a positive regulation of AR. In addition, based on the homology between cyclin D1 and p35, the protein interaction between p35 and AR was also identified. Interestingly, we found that overexpression of Cdk5 or p35 in prostate cancer cells significantly decreased the association of cyclin D1 and AR. The ability of the AR to activate endogenous target gene expression was inhibited in the presence of cyclin D1. However, the interaction between Cdk5 and AR significantly increased endogenous PSA expression and PSA secretion. Furthermore, Cdk5 inhibition by siRNA decreased the expression of PSA protein. In conclusion, we suggest that Cdk5 might modulate AR transactivation in prostate cancer through competition with cyclin D1. Therefore, Cdk5 becomes a future candidate of therapeutic target for prostate cancer.
其他識別: U0005-1708200819230300
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