Please use this identifier to cite or link to this item:
標題: Cdk5參與攝護腺癌細胞中interleukin-6促進之STAT3 serine727與AR serine81 磷酸化以及AR蛋白活化
Cdk5 involves interleukin-6-induced phosphorylation of serine727 STAT3, serine81 AR, and AR activation in prostate cancer cells
作者: 李培齊
Li, Pei-Chi
關鍵字: Interleukin-6
serine 81 phosphorylation of the androgen receptor
出版社: 生命科學系所
引用: 1. Kishimoto, T. (2010) IL-6: from its discovery to clinical applications. International immunology 22, 347-352 2. Yamasaki, K., Taga, T., Hirata, Y., Yawata, H., Kawanishi, Y., Seed, B., Taniguchi, T., Hirano, T., and Kishimoto, T. (1988) Cloning and expression of the human interleukin-6 (BSF-2/IFN beta 2) receptor. Science 241, 825-828 3. Martin, W. J., and Miller, J. F. (1968) Cell to cell interaction in the immune response. IV. Site of action of antilymphocyte globulin. The Journal of experimental medicine 128, 855-874 4. Claman, H. N., Chaperon, E. A., and Selner, J. C. (1968) Thymus-marrow immunocompetence. 3. The requirement for living thymus cells. Proceedings of the Society for Experimental Biology and Medicine. Society for Experimental Biology and Medicine 127, 462-466 5. Kishimoto, T. (1985) Factors affecting B-cell growth and differentiation. Annual review of immunology 3, 133-157 6. Hibi, M., Murakami, M., Saito, M., Hirano, T., Taga, T., and Kishimoto, T. (1990) Molecular cloning and expression of an IL-6 signal transducer, gp130. Cell 63, 1149-1157 7. Taga, T., Hibi, M., Hirata, Y., Yamasaki, K., Yasukawa, K., Matsuda, T., Hirano, T., and Kishimoto, T. (1989) Interleukin-6 triggers the association of its receptor with a possible signal transducer, gp130. Cell 58, 573-581 8. Akira, S., Isshiki, H., Sugita, T., Tanabe, O., Kinoshita, S., Nishio, Y., Nakajima, T., Hirano, T., and Kishimoto, T. (1990) A nuclear factor for IL-6 expression (NF-IL6) is a member of a C/EBP family. The EMBO journal 9, 1897-1906 9. Akira, S., Nishio, Y., Inoue, M., Wang, X. J., Wei, S., Matsusaka, T., Yoshida, K., Sudo, T., Naruto, M., and Kishimoto, T. (1994) Molecular cloning of APRF, a novel IFN-stimulated gene factor 3 p91-related transcription factor involved in the gp130-mediated signaling pathway. Cell 77, 63-71 10. Endo, T. A., Masuhara, M., Yokouchi, M., Suzuki, R., Sakamoto, H., Mitsui, K., Matsumoto, A., Tanimura, S., Ohtsubo, M., Misawa, H., Miyazaki, T., Leonor, N., Taniguchi, T., Fujita, T., Kanakura, Y., Komiya, S., and Yoshimura, A. (1997) A new protein containing an SH2 domain that inhibits JAK kinases. Nature 387, 921-924 11. Naka, T., Narazaki, M., Hirata, M., Matsumoto, T., Minamoto, S., Aono, A., Nishimoto, N., Kajita, T., Taga, T., Yoshizaki, K., Akira, S., and Kishimoto, T. (1997) Structure and function of a new STAT-induced STAT inhibitor. Nature 387, 924-929 12. Starr, R., Willson, T. A., Viney, E. M., Murray, L. J., Rayner, J. R., Jenkins, B. J., Gonda, T. J., Alexander, W. S., Metcalf, D., Nicola, N. A., and Hilton, D. J. (1997) A family of cytokine-inducible inhibitors of signalling. Nature 387, 917-921 13. Kishimoto, T., and Ishizaka, K. (1971) Regulation of antibody response in vitro. Suppression of secondary response by anti-immunoglobulin heavy chains. Journal of immunology 107, 1567-1575 14. Hong, D. S., Angelo, L. S., and Kurzrock, R. (2007) Interleukin-6 and its receptor in cancer: implications for translational therapeutics. Cancer 110, 1911-1928 15. Chun, J. Y., Nadiminty, N., Dutt, S., Lou, W., Yang, J. C., Kung, H. J., Evans, C. P., and Gao, A. C. (2009) Interleukin-6 regulates androgen synthesis in prostate cancer cells. Clinical cancer research : an official journal of the American Association for Cancer Research 15, 4815-4822 16. Siegall, C. B., Schwab, G., Nordan, R. P., FitzGerald, D. J., and Pastan, I. (1990) Expression of the interleukin 6 receptor and interleukin 6 in prostate carcinoma cells. Cancer research 50, 7786-7788 17. Lee, S. O., Lou, W., Hou, M., de Miguel, F., Gerber, L., and Gao, A. C. (2003) Interleukin-6 promotes androgen-independent growth in LNCaP human prostate cancer cells. Clinical cancer research : an official journal of the American Association for Cancer Research 9, 370-376 18. Ueda, T., Bruchovsky, N., and Sadar, M. D. (2002) Activation of the androgen receptor N-terminal domain by interleukin-6 via MAPK and STAT3 signal transduction pathways. The Journal of biological chemistry 277, 7076-7085 19. Aaronson, D. S., Muller, M., Neves, S. R., Chung, W. C., Jayaram, G., Iyengar, R., and Ram, P. T. (2007) An androgen-IL-6-Stat3 autocrine loop re-routes EGF signal in prostate cancer cells. Molecular and cellular endocrinology 270, 50-56 20. Zhu, M. L., and Kyprianou, N. (2008) Androgen receptor and growth factor signaling cross-talk in prostate cancer cells. Endocrine-related cancer 15, 841-849 21. Morley, J. E., and Perry, H. M., 3rd. (1999) Androgen deficiency in aging men. The Medical clinics of North America 83, 1279-1289, vii 22. Feldman, B. J., and Feldman, D. (2001) The development of androgen-independent prostate cancer. Nature reviews. Cancer 1, 34-45 23. Isaacs, J. T., and Isaacs, W. B. (2004) Androgen receptor outwits prostate cancer drugs. Nature medicine 10, 26-27 24. 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. (2002) Androgen receptor phosphorylation. Regulation and identification of the phosphorylation sites. The Journal of biological chemistry 277, 29304-29314 25. Zhou, Z. X., Kemppainen, J. A., and Wilson, E. M. (1995) Identification of three proline-directed phosphorylation sites in the human androgen receptor. Molecular endocrinology 9, 605-615 26. Zhu, Z., Becklin, R. R., Desiderio, D. M., and Dalton, J. T. (2001) Identification of a novel phosphorylation site in human androgen receptor by mass spectrometry. Biochemical and biophysical research communications 284, 836-844 27. Adams, M., Meijer, O. C., Wang, J., Bhargava, A., and Pearce, D. (2003) Homodimerization of the glucocorticoid receptor is not essential for response element binding: activation of the phenylethanolamine N-methyltransferase gene by dimerization-defective mutants. Molecular endocrinology 17, 2583-2592 28. Coon, J. J., Ueberheide, B., Syka, J. E., Dryhurst, D. D., Ausio, J., Shabanowitz, J., and Hunt, D. F. (2005) Protein identification using sequential ion/ion reactions and tandem mass spectrometry. Proceedings of the National Academy of Sciences of the United States of America 102, 9463-9468 29. Guo, Z., Dai, B., Jiang, T., Xu, K., Xie, Y., Kim, O., Nesheiwat, I., Kong, X., Melamed, J., Handratta, V. D., Njar, V. C., Brodie, A. M., Yu, L. R., Veenstra, T. D., Chen, H., and Qiu, Y. (2006) Regulation of androgen receptor activity by tyrosine phosphorylation. Cancer cell 10, 309-319 30. Kraus, S., Gioeli, D., Vomastek, T., Gordon, V., and Weber, M. J. (2006) Receptor for activated C kinase 1 (RACK1) and Src regulate the tyrosine phosphorylation and function of the androgen receptor. Cancer research 66, 11047-11054 31. Ponguta, L. A., Gregory, C. W., French, F. S., and Wilson, E. M. (2008) Site-specific androgen receptor serine phosphorylation linked to epidermal growth factor-dependent growth of castration-recurrent prostate cancer. The Journal of biological chemistry 283, 20989-21001 32. Abreu-Martin, M. T., Chari, A., Palladino, A. A., Craft, N. A., and Sawyers, C. L. (1999) Mitogen-activated protein kinase kinase kinase 1 activates androgen receptor-dependent transcription and apoptosis in prostate cancer. Molecular and cellular biology 19, 5143-5154 33. Feng, H., Cheng, A. S., Tsang, D. P., Li, M. S., Go, M. Y., Cheung, Y. S., Zhao, G. J., Ng, S. S., Lin, M. C., Yu, J., Lai, P. B., To, K. F., and Sung, J. J. (2011) Cell cycle-related kinase is a direct androgen receptor-regulated gene that drives beta-catenin/T cell factor-dependent hepatocarcinogenesis. The Journal of clinical investigation 121, 3159-3175 34. Hsu, F. N., Yang, M. S., Lin, E., Tseng, C. F., and Lin, H. (2011) The significance of Her2 on androgen receptor protein stability in the transition of androgen requirement in prostate cancer cells. American journal of physiology. Endocrinology and metabolism 300, E902-908 35. Mellinghoff, I. K., Vivanco, I., Kwon, A., Tran, C., Wongvipat, J., and Sawyers, C. L. (2004) HER2/neu kinase-dependent modulation of androgen receptor function through effects on DNA binding and stability. Cancer cell 6, 517-527 36. Sherwood, E. R., Van Dongen, J. L., Wood, C. G., Liao, S., Kozlowski, J. M., and Lee, C. (1998) Epidermal growth factor receptor activation in androgen-independent but not androgen-stimulated growth of human prostatic carcinoma cells. British journal of cancer 77, 855-861 37. Gerdes, M. J., Dang, T. D., Larsen, M., and Rowley, D. R. (1998) Transforming growth factor-beta1 induces nuclear to cytoplasmic distribution of androgen receptor and inhibits androgen response in prostate smooth muscle cells. Endocrinology 139, 3569-3577 38. Kumar, V. L., Majumder, P. K., Murty, O. P., and Kumar, V. (1998) Detection of receptor transcripts for androgen, epidermal growth factor and basic fibroblast growth factor in human prostate postmortem. International urology and nephrology 30, 301-304 39. Culig, Z., Hobisch, A., Cronauer, M. V., Hittmair, A., Radmayr, C., Bartsch, G., and Klocker, H. (1995) Activation of the androgen receptor by polypeptide growth factors and cellular regulators. World journal of urology 13, 285-289 40. Chen, S., Xu, Y., Yuan, X., Bubley, G. J., and Balk, S. P. (2006) Androgen receptor phosphorylation and stabilization in prostate cancer by cyclin-dependent kinase 1. Proceedings of the National Academy of Sciences of the United States of America 103, 15969-15974 41. Liu, S., Yuan, Y., Okumura, Y., Shinkai, N., and Yamauchi, H. (2010) Camptothecin disrupts androgen receptor signaling and suppresses prostate cancer cell growth. Biochemical and biophysical research communications 394, 297-302 42. Tsai, L. H., Takahashi, T., Caviness, V. S., Jr., and Harlow, E. (1993) Activity and expression pattern of cyclin-dependent kinase 5 in the embryonic mouse nervous system. Development 119, 1029-1040 43. Sellers, W. R., and Fisher, D. E. (1999) Apoptosis and cancer drug targeting. The Journal of clinical investigation 104, 1655-1661 44. Weishaupt, J. H., Neusch, C., and Bahr, M. (2003) Cyclin-dependent kinase 5 (CDK5) and neuronal cell death. Cell and tissue research 312, 1-8 45. Tsai, L. H., Delalle, I., Caviness, V. S., Jr., Chae, T., and Harlow, E. (1994) p35 is a neural-specific regulatory subunit of cyclin-dependent kinase 5. Nature 371, 419-423 46. Humbert, S., Dhavan, R., and Tsai, L. (2000) p39 activates cdk5 in neurons, and is associated with the actin cytoskeleton. Journal of cell science 113 ( Pt 6), 975-983 47. Su, S. C., and Tsai, L. H. (2011) Cyclin-dependent kinases in brain development and disease. Annual review of cell and developmental biology 27, 465-491 48. Dhavan, R., and Tsai, L. H. (2001) A decade of CDK5. Nature reviews. Molecular cell biology 2, 749-759 49. Lee, M. S., Kwon, Y. T., Li, M., Peng, J., Friedlander, R. M., and Tsai, L. H. (2000) Neurotoxicity induces cleavage of p35 to p25 by calpain. Nature 405, 360-364 50. Zukerberg, L. R., Patrick, G. N., Nikolic, M., Humbert, S., Wu, C. L., Lanier, L. M., Gertler, F. B., Vidal, M., Van Etten, R. A., and Tsai, L. H. (2000) Cables links Cdk5 and c-Abl and facilitates Cdk5 tyrosine phosphorylation, kinase upregulation, and neurite outgrowth. Neuron 26, 633-646 51. Ubeda, M., Kemp, D. M., and Habener, J. F. (2004) Glucose-induced expression of the cyclin-dependent protein kinase 5 activator p35 involved in Alzheimer''s disease regulates insulin gene transcription in pancreatic beta-cells. Endocrinology 145, 3023-3031 52. Lilja, L., Yang, S. N., Webb, D. L., Juntti-Berggren, L., Berggren, P. O., and Bark, C. (2001) Cyclin-dependent kinase 5 promotes insulin exocytosis. The Journal of biological chemistry 276, 34199-34205 53. Lilja, L., Johansson, J. U., Gromada, J., Mandic, S. A., Fried, G., Berggren, P. O., and Bark, C. (2004) Cyclin-dependent kinase 5 associated with p39 promotes Munc18-1 phosphorylation and Ca(2+)-dependent exocytosis. The Journal of biological chemistry 279, 29534-29541 54. Musa, F. R., Tokuda, M., Kuwata, Y., Ogawa, T., Tomizawa, K., Konishi, R., Takenaka, I., and Hatase, O. (1998) Expression of cyclin-dependent kinase 5 and associated cyclins in Leydig and Sertoli cells of the testis. Journal of andrology 19, 657-666 55. Musa, F. R., Takenaka, I., Konishi, R., and Tokuda, M. (2000) 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. Journal of andrology 21, 392-402 56. Zhang, Q., Ahuja, H. S., Zakeri, Z. F., and Wolgemuth, D. J. (1997) Cyclin-dependent kinase 5 is associated with apoptotic cell death during development and tissue remodeling. Developmental biology 183, 222-233 57. Chen, F., Wang, Q., Wang, X., and Studzinski, G. P. (2004) Up-regulation of Egr1 by 1,25-dihydroxyvitamin D3 contributes to increased expression of p35 activator of cyclin-dependent kinase 5 and consequent onset of the terminal phase of HL60 cell differentiation. Cancer research 64, 5425-5433 58. Goodyear, S., and Sharma, M. C. (2007) Roscovitine regulates invasive breast cancer cell (MDA-MB231) proliferation and survival through cell cycle regulatory protein cdk5. Experimental and molecular pathology 82, 25-32 59. Selvendiran, K., Koga, H., Ueno, T., Yoshida, T., Maeyama, M., Torimura, T., Yano, H., Kojiro, M., and Sata, M. (2006) Luteolin promotes degradation in signal transducer and activator of transcription 3 in human hepatoma cells: an implication for the antitumor potential of flavonoids. Cancer research 66, 4826-4834 60. Kim, E., Chen, F., Wang, C. C., and Harrison, L. E. (2006) CDK5 is a novel regulatory protein in PPARgamma ligand-induced antiproliferation. International journal of oncology 28, 191-194 61. Lin, H., Chen, M. C., Chiu, C. Y., Song, Y. M., and Lin, S. Y. (2007) Cdk5 regulates STAT3 activation and cell proliferation in medullary thyroid carcinoma cells. The Journal of biological chemistry 282, 2776-2784 62. Strock, C. J., Park, J. I., Nakakura, E. K., Bova, G. S., Isaacs, J. T., Ball, D. W., and Nelkin, B. D. (2006) Cyclin-dependent kinase 5 activity controls cell motility and metastatic potential of prostate cancer cells. Cancer research 66, 7509-7515 63. Lin, H., Juang, J. L., and Wang, P. S. (2004) Involvement of Cdk5/p25 in digoxin-triggered prostate cancer cell apoptosis. The Journal of biological chemistry 279, 29302-29307 64. Kino, T., Ichijo, T., Amin, N. D., Kesavapany, S., Wang, Y., Kim, N., Rao, S., Player, A., Zheng, Y. L., Garabedian, M. J., Kawasaki, E., Pant, H. C., and Chrousos, G. P. (2007) Cyclin-dependent kinase 5 differentially regulates the transcriptional activity of the glucocorticoid receptor through phosphorylation: clinical implications for the nervous system response to glucocorticoids and stress. Molecular endocrinology 21, 1552-1568 65. Fu, A. K., Fu, W. Y., Ng, A. K., Chien, W. W., Ng, Y. P., Wang, J. H., and Ip, N. Y. (2004) Cyclin-dependent kinase 5 phosphorylates signal transducer and activator of transcription 3 and regulates its transcriptional activity. Proceedings of the National Academy of Sciences of the United States of America 101, 6728-6733 66. Hsu, F. N., Chen, M. C., Chiang, M. C., Lin, E., Lee, Y. T., Huang, P. H., Lee, G. S., and Lin, H. (2011) Regulation of androgen receptor and prostate cancer growth by cyclin-dependent kinase 5. The Journal of biological chemistry 286, 33141-33149 67. Lee, S. O., Lou, W., Johnson, C. S., Trump, D. L., and Gao, A. C. (2004) Interleukin-6 protects LNCaP cells from apoptosis induced by androgen deprivation through the Stat3 pathway. The Prostate 60, 178-186 68. Lin, H., Chen, M. C., and Ku, C. T. (2009) Cyclin-dependent kinase 5 regulates steroidogenic acute regulatory protein and androgen production in mouse Leydig cells. Endocrinology 150, 396-403 69. Chen, T., Wang, L. H., and Farrar, W. L. (2000) Interleukin 6 activates androgen receptor-mediated gene expression through a signal transducer and activator of transcription 3-dependent pathway in LNCaP prostate cancer cells. Cancer research 60, 2132-2135 70. Honda, R., Tanaka, H., and Yasuda, H. (1997) Oncoprotein MDM2 is a ubiquitin ligase E3 for tumor suppressor p53. FEBS letters 420, 25-27 71. Fang, S., Jensen, J. P., Ludwig, R. L., Vousden, K. H., and Weissman, A. M. (2000) Mdm2 is a RING finger-dependent ubiquitin protein ligase for itself and p53. The Journal of biological chemistry 275, 8945-8951 72. Linn, D. E., Yang, X., Xie, Y., Alfano, A., Deshmukh, D., Wang, X., Shimelis, H., Chen, H., Li, W., Xu, K., Chen, M., and Qiu, Y. (2012) Differential regulation of androgen receptor by PIM-1 kinases via phosphorylation-dependent recruitment of distinct ubiquitin E3 ligases. The Journal of biological chemistry 287, 22959-22968 73. Lin, H. K., Wang, L., Hu, Y. C., Altuwaijri, S., and Chang, C. (2002) Phosphorylation-dependent ubiquitylation and degradation of androgen receptor by Akt require Mdm2 E3 ligase. The EMBO journal 21, 4037-4048 74. Xiao, B. Y., and Li, G. Y. (2004) [Ubiquitin-proteasome pathway]. Zhong nan da xue xue bao. Yi xue ban = Journal of Central South University. Medical sciences 29, 230-232 75. Courapied, S., Sellier, H., de Carne Trecesson, S., Vigneron, A., Bernard, A. C., Gamelin, E., Barre, B., and Coqueret, O. (2010) The cdk5 kinase regulates the STAT3 transcription factor to prevent DNA damage upon topoisomerase I inhibition. The Journal of biological chemistry 285, 26765-26778 76. He, Y., Kastin, A. J., Hsuchou, H., and Pan, W. (2009) The Cdk5/p35 kinases modulate leptin-induced STAT3 signaling. Journal of molecular neuroscience : MN 39, 49-58 77. Hara, T., Nakamura, K., Araki, H., Kusaka, M., and Yamaoka, M. (2003) Enhanced androgen receptor signaling correlates with the androgen-refractory growth in a newly established MDA PCa 2b-hr human prostate cancer cell subline. Cancer research 63, 5622-5628 78. Suzuki, H., Ueda, T., Ichikawa, T., and Ito, H. (2003) Androgen receptor involvement in the progression of prostate cancer. Endocrine-related cancer 10, 209-216 79. Chen, C. D., Welsbie, D. S., Tran, C., Baek, S. H., Chen, R., Vessella, R., Rosenfeld, M. G., and Sawyers, C. L. (2004) Molecular determinants of resistance to antiandrogen therapy. Nature medicine 10, 33-39 80. McGlynn, K. A., Tsao, L., Hsing, A. W., Devesa, S. S., and Fraumeni, J. F., Jr. (2001) International trends and patterns of primary liver cancer. International journal of cancer. Journal international du cancer 94, 290-296 81. Greenlee, R. T., Hill-Harmon, M. B., Murray, T., and Thun, M. (2001) Cancer statistics, 2001. CA: a cancer journal for clinicians 51, 15-36 82. Lee, D. K., and Chang, C. (2003) Endocrine mechanisms of disease: Expression and degradation of androgen receptor: mechanism and clinical implication. The Journal of clinical endocrinology and metabolism 88, 4043-4054 83. Liebl, J., Weitensteiner, S. B., Vereb, G., Takacs, L., Furst, R., Vollmar, A. M., and Zahler, S. (2010) Cyclin-dependent kinase 5 regulates endothelial cell migration and angiogenesis. The Journal of biological chemistry 285, 35932-35943 84. Hsing, A. W. (2001) Hormones and prostate cancer: what''s next? Epidemiologic reviews 23, 42-58 85. Chen, M. C., Huang, C. Y., Hsu, S. L., Lin, E., Ku, C. T., Lin, H., and Chen, C. M. (2012) Retinoic Acid Induces Apoptosis of Prostate Cancer DU145 Cells through Cdk5 Overactivation. Evidence-based complementary and alternative medicine : eCAM 2012, 580736 86. Wang, H. Y., Lin, W. Y., Chen, M. C., Lin, T., Chao, C. H., Hsu, F. N., Lin, E., Huang, C. Y., Luo, T. Y., and Lin, H. (2013) Inhibitory effects of Rhenium-188-labeled Herceptin on prostate cancer cell growth: a possible radioimmunotherapy to prostate carcinoma. International journal of radiation biology 89, 346-355 87. Quintanilla, R. A., Orellana, D. I., Gonzalez-Billault, C., and Maccioni, R. B. (2004) Interleukin-6 induces Alzheimer-type phosphorylation of tau protein by deregulating the cdk5/p35 pathway. Experimental cell research 295, 245-257 88. Haenszel, W., and Kurihara, M. (1968) Studies of Japanese migrants. I. Mortality from cancer and other diseases among Japanese in the United States. Journal of the National Cancer Institute 40, 43-68 89. Wilson, J. D. (1972) Recent studies on the mechanism of action of testosterone. The New England journal of medicine 287, 1284-1291 90. Hsiao, P. W., Lin, D. L., Nakao, R., and Chang, C. (1999) The linkage of Kennedy''s neuron disease to ARA24, the first identified androgen receptor polyglutamine region-associated coactivator. The Journal of biological chemistry 274, 20229-20234 91. Yeh, S., Lin, H. K., Kang, H. Y., Thin, T. H., Lin, M. F., and Chang, C. (1999) From HER2/Neu signal cascade to androgen receptor and its coactivators: a novel pathway by induction of androgen target genes through MAP kinase in prostate cancer cells. Proceedings of the National Academy of Sciences of the United States of America 96, 5458-5463
摘要: 在西方國家攝護腺癌為男性癌症死因第二位,其造成的死亡人數僅次於肺癌。信號傳導和轉錄活化蛋白 (Signal transducer and activator of transcription 3, STAT3) 為一個重要的轉錄因子,它被發現會過度表現在許多癌症細胞中。在過去的文獻中指出,STAT3的轉錄活性必須依靠其Tyrosine 705的磷酸化使STAT3蛋白形成二聚體,進入細胞核內結合至DNA promoter轉錄下游基因。然而,STAT3的Serine 727磷酸化位點也扮演著關鍵的角色。在許多刺激下,磷酸化Serine727可讓STAT3本身的轉錄活性達到最大值,並作為雄性激素受體 (androgen receptor, AR) 的transcriptional co-activator調控AR下游基因表現。先前攝護腺癌症的研究知道細胞介素 (Interleukin-6, IL-6) 的刺激會增加S727-STAT3磷酸化並促進與AR蛋白的交互作用。我們的結果發現,IL-6的刺激確實可活化S727-STAT3並進一步調控Serine 81 AR磷酸化。另一方面,在我們實驗室的研究指出Cdk5可正向調控S727-STAT3的磷酸化並促進攝護腺癌細胞的生長。此外,Cdk5同時也可以促進S81-AR磷酸化,增加Cdk5與AR蛋白的交互作用,使得AR更加穩定。在本篇研究中我們發現除了S727-STAT3的活化能讓S81-AR磷酸化,使得AR蛋白更加的穩定,進而增加細胞核內AR的累積和促進AR的轉錄活性,同時我們也發現,STAT3的S727A位點突變 (Serine→Alanine) 可使AR與E3 ligase Mdm2蛋白之間的交互作用增加,表示AR可能會經由轉譯後修飾Ubiquitination導致AR蛋白的降解。我們額外觀察到透過IL-6的刺激會造成Tyrosine 15 Cdk5 (Y15-Cdk5)磷酸化上升,也受到IL-6路徑下游Jak2蛋白抑制劑AG490的作用而造成Y15-Cdk5磷酸化下降,進而影響STAT3和AR交互作用。綜合以上結果,磷酸化的S727-STAT3對於S81-AR活化扮演非常重要的角色,且Cdk5也參與在IL-6刺激的路徑中。
Prostate cancer is the most common type of cancer in men and ranks the second place in cancer-related deaths. Signal transducers and activators of transcription 3 (STAT3), which is constitutively activated in a wide variety of human cancers, in-cluding prostate cancer. STAT3 contains a DNA binding, a transactivation, and a SH2 domain, and is activated by tyrosine 705 (Y705) phosphorylation which re-sults in homodimerization through SH2-phosphotyrosyl interaction and transloca-tion into the nucleus, where it binds to promoter transactivating downstream genes. In addition to Y705 phosphorylation, phosphorylation of another conserved STAT3 residue, Serine 727 (S727), has also been documented to activate STAT3 signaling. In LNCaP cells, a prostate cancer cell line, which expresses AR and is androgen-dependent, Interleukin-6 (IL-6), a cytokine, can activate the androgen receptor and promotes proliferation. Previous studies have shown the cross talk between STAT3 and AR showing that IL-6 activates the androgen receptor in a STAT3 dependent manner. Here, we find that IL-6 stimulates S727 phosphoryla-tion of STAT3, and further more upregulates AR expression, especially Serine 81 (S81) phosphorylate. On the other hand, our lab previous data shown that Cdk5 enables phosphorylation of AR at S81 site through direct biochemical interaction and, therefore, results in the stabilization of AR proteins. The positive regulations of Cdk5-AR on cell growth are also determined in vitro and in vivo. Cdk5 also can positively regulates S727 phosphorylation and promotes prostate cancer cell pro-liferation. In the present study, we found S727 of STAT3 activation plays a critical role for S81-AR phosphorylation, to promote AR stabilize its protein level, and causes accumulation of AR protein into nuclear localization and subsequent tran-scription activation. We also found that mutant S727-STAT3 (S727A) increased the association of AR and Mdm2, which is turn induced AR degradation through proteasome-mediated pathway, resulting in AR protein expression decrease. Moreover, IL-6 induced Tyrosine 15 (Y15) phosphorylation of Cdk5, and which was inhibited by AG490. We also found that mutant Y15-Cdk5 (Y15F) reduced both of S727-STAT3 and S81-AR phosphorylation, resulting decrease STAT3-AR interaction. These finding demonstrate that IL-6 induces S727-STAT3 and further to activate AR protein through S81 phosphorylation site, as well as, Cdk5 also in-volved in the IL-6 stimulated pathway.
其他識別: U0005-2805201314490000
Appears in Collections:生命科學系所



Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.