Please use this identifier to cite or link to this item: http://hdl.handle.net/11455/22500
標題: Her2經由影響Cdk5激酶活性及AR轉錄活化以調控人類攝護腺癌細胞生長
Her2 modulates Cdk5-dependent AR activation and cell proliferation in human prostate cancer
作者: 許馥甯
Hsu, Fu-Ning
關鍵字: androgen receptor;雄性激素受體;prostate cancer;攝護腺癌
出版社: 生命科學系所
引用: 1. Brook, C. G. D. &. Marshall, N. J. Endocrinology, 4th edition, Blackwell Science Press, 2001. 2. Campbell, N. A. &. Reece, J. N. Biology, 6th edition, p. 980~982, 987. Benjamin Cummings Press, 2002. 3. 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. 4. Greenlee, R. T., Hill-Harmon, M. B., Murray, T., and Thun, M. Cancer statistics, 2001. Ca Cancer J Clin, 51: 15-36, 2001. 5. Hsing, A. W. Hormones and prostate cancer: what''s next? Epidemiol Rev, 23: 42-58, 2001. 6. Mellinghoff, I. K., Vivanco, I., Kwon, A., Tran, C., Wongvipat, J., and Sawyers, C. L. HER2/neu kinase-dependent modulation of androgen receptor function through effects on DNA binding and stability. Cancer Cell, 6: 517-527, 2004. 7. Culig, Z. and Bartsch, G. Androgen axis in prostate cancer. J Cell Biochem, 99: 373-381, 2006. 8. Hamalainen, E., Adlercreutz, H., Puska, P., and Pietinen, P. Diet and serum sex hormones in healthy men. J Steroid Biochem, 20: 459-464, 1984. 9. Dorgan, J. F., Judd, J. T., Longcope, C., Brown, C., Schatzkin, A., Clevidence, B. A., Campbell, W. S., Nair, P. P., Franz, C., Kahle, L., and Taylor, P. R. Effects of dietary fat and fiber on plasma and urine androgens and estrogens in men: a controlled feeding study. Am J Clin Nutr, 64: 850-855, 1996. 10. Gann, P. H., Hennekens, C. H., Ma, J., Longcope, C., and Stampfer, M. J. Prospective study of sex hormone levels and risk of prostate cancer. J Natl Cancer Inst, 88: 1118-1126, 1996. 11. 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. 12. Isaacs, J. T. and Isaacs, W. B. Androgen receptor outwits prostate cancer drugs. Nat Med, 10: 26-27, 2004. 13. 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. 14. Hara, T., Nakamura, K., Araki, H., Kusaka, M., and Yamaoka, M. Enhanced androgen receptor signaling correlates with the androgen-refractory growth in a newly established MDA PCa 2b-hr human prostate cancer cell subline. Cancer Res, 63: 5622-5628, 2003. 15. Chen, C. D., Welsbie, D. S., Tran, C., Baek, S. H., Chen, R., Vessella, R., Rosenfeld, M. G., and Sawyers, C. L. Molecular determinants of resistance to antiandrogen therapy. Nat Med, 10: 33-39, 2004. 16. Zegarra-Moro, O. L., Schmidt, L. J., Huang, H., and Tindall, D. J. Disruption of androgen receptor function inhibits proliferation of androgen-refractory prostate cancer cells. Cancer Res, 62: 1008-1013, 2002. 17. Brown, C. J., Goss, S. J., Lubahn, D. B., Joseph, D. R., Wilson, E. M., French, F. S., and Willard, H. F. Androgen receptor locus on the human X chromosome: regional localization to Xq11-12 and description of a DNA polymorphism. Am J Hum Genet, 44: 264-269, 1989. 18. Culig, Z. Role of the androgen receptor axis in prostate cancer. Urology, 62: 21-26, 2003. 19. Haenszel, W. and Kurihara, M. Studies of Japanese migrants. I. Mortality from cancer and other diseases among Japanese in the United States. J Natl Cancer Inst, 40: 43-68, 1968. 20. 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. 21. Wilson, J. D. Recent studies on the mechanism of action of testosterone. N Engl J Med, 287: 1284-1291, 1972. 22. Hsiao, P. W., Lin, D. L., Nakao, R., and Chang, C. The linkage of Kennedy''s neuron disease to ARA24, the first identified androgen receptor polyglutamine region-associated coactivator. J Biol Chem, 274: 20229-20234, 1999. 23. Yeh, S., Lin, H. K., Kang, H. Y., Thin, T. H., Lin, M. F., and Chang, C. 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. Proc Natl Acad Sci USA, 96: 5458-5463, 1999. 24. Fujimoto, N., Yeh, S., Kang, H. Y., Inui, S., Chang, H. C., Mizokami, A., and Chang, C. Cloning and characterization of androgen receptor coactivator, ARA55, in human prostate. J Biol Chem, 274: 8316-8321, 1999. 25. Yeh, S. and Chang, C. Cloning and characterization of a specific coactivator, ARA70, for the androgen receptor in human prostate cells. Proc Natl Acad Sci USA, 93: 5517-5521, 1996. 26. Wang, X., Yeh, S., Wu, G., Hsu, C. L., Wang, L., Chiang, T., Yang, Y., Guo, Y., and Chang, C. Identification and characterization of a novel androgen receptor coregulator ARA267-alpha in prostate cancer cells. J Biol Chem, 276: 40417-40423, 2001. 27. Aarnisalo, P., Palvimo, J. J., and Janne, O. A. CREB-binding protein in androgen receptor-mediated signaling. Proc Natl Acad Sci USA, 95: 2122-2127, 1998. 28. Fu, M., Wang, C., Reutens, A. T., Wang, J., Angeletti, R. H., Siconolfi-Baez, L., Ogryzko, V., Avantaggiati, M. L., and Pestell, R. G. p300 and p300/cAMP-response element-binding protein-associated factor acetylate the androgen receptor at sites governing hormone-dependent transactivation. J Biol Chem, 275: 20853-20860, 2000. 29. Debes, J. D., Schmidt, L. J., Huang, H., and Tindall, D. J. p300 mediates androgen-independent transactivation of the androgen receptor by interleukin 6. Cancer Res, 62: 5632-5636, 2002. 30. Berrevoets, C. A., Doesburg, P., Steketee, K., Trapman, J., and Brinkmann, A. O. Functional interactions of the AF-2 activation domain core region of the human androgen receptor with the amino-terminal domain and with the transcriptional coactivator TIF2 (transcriptional intermediary factor2). Mol Endocrinol, 12: 1172-1183, 1998. 31. Ikonen, T., Palvimo, J. J., and Janne, O. A. Interaction between the amino- and carboxyl-terminal regions of the rat androgen receptor modulates transcriptional activity and is influenced by nuclear receptor coactivators. J Biol Chem, 272: 29821-29828, 1997. 32. Hsiao, P. W. and Chang, C. Isolation and characterization of ARA160 as the first androgen receptor N-terminal-associated coactivator in human prostate cells. J Biol Chem, 274: 22373-22379, 1999. 33. Rau, K. M., Kang, H. Y., Cha, T. L., Miller, S. A., and Hung, M. C. The mechanisms and managements of hormone-therapy resistance in breast and prostate cancers. Endocr Relat Cancer, 12: 511-532, 2005. 34. Glantz, G. M. Cirrhosis and Carcinoma of the Prostate Gland. J Urol, 91: 291-293, 1964. 35. 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. 36. Thompson, I. M., Pauler, D. K., Goodman, P. J., Tangen, C. M., Lucia, M. S., Parnes, H. L., Minasian, L. M., Ford, L. G., Lippman, S. M., Crawford, E. D., Crowley, J. J., and Coltman, C. A., Jr. Prevalence of prostate cancer among men with a prostate-specific antigen level < or =4.0 ng per milliliter. N Engl J Med, 350: 2239-2246, 2004. 37. Liu, Y., Majumder, S., McCall, W., Sartor, C. I., Mohler, J. L., Gregory, C. W., Earp, H. S., and Whang, Y. E. Inhibition of HER-2/neu kinase impairs androgen receptor recruitment to the androgen responsive enhancer. Cancer Res, 65: 3404-3409, 2005. 38. Chu, T. M. Prostate-specific antigen and early detection of prostate cancer. Tumour Biol, 18: 123-134, 1997. 39. Lee, C. T. and Oesterling, J. E. Diagnostic markers of prostate cancer: utility of prostate-specific antigen in diagnosis and staging. Semin Surg Oncol, 11: 23-35, 1995. 40. Webber, M. M., Waghray, A., and Bello, D. Prostate-specific antigen, a serine protease, facilitates human prostate cancer cell invasion. Clin Cancer Res, 1: 1089-1094, 1995. 41. Olayioye, M. A., Neve, R. M., Lane, H. A., and Hynes, N. E. The ErbB signaling network: receptor heterodimerization in development and cancer. EMBO J, 19: 3159-3167, 2000. 42. Roskoski, R., Jr. The ErbB/HER receptor protein-tyrosine kinases and cancer. Biochem Biophys Res Commun, 319: 1-11, 2004. 43. Graus-Porta, D., Beerli, R. R., Daly, J. M., and Hynes, N. E. ErbB-2, the preferred heterodimerization partner of all ErbB receptors, is a mediator of lateral signaling. EMBO J, 16: 1647-1655, 1997. 44. Rowinsky, E. K. Signal events: Cell signal transduction and its inhibition in cancer. Oncologist, 8 Suppl 3: 5-17, 2003. 45. Peles, E. and Yarden, Y. Neu and its ligands: from an oncogene to neural factors. Bioessays, 15: 815-824, 1993. 46. Riese, D. J., 2nd and Stern, D. F. Specificity within the EGF family/ErbB receptor family signaling network. Bioessays, 20: 41-48, 1998. 47. Busfield, S. J., Michnick, D. A., Chickering, T. W., Revett, T. L., Ma, J., Woolf, E. A., Comrack, C. A., Dussault, B. J., Woolf, J., Goodearl, A. D., and Gearing, D. P. Characterization of a neuregulin-related gene, Don-1, that is highly expressed in restricted regions of the cerebellum and hippocampus. Mol Cell Biol, 17: 4007-4014, 1997. 48. Carraway, K. L., 3rd, Weber, J. L., Unger, M. J., Ledesma, J., Yu, N., Gassmann, M., and Lai, C. Neuregulin-2, a new ligand of ErbB3/ErbB4-receptor tyrosine kinases. Nature, 387: 512-516, 1997. 49. Harari, D., Tzahar, E., Romano, J., Shelly, M., Pierce, J. H., Andrews, G. C., and Yarden, Y. Neuregulin-4: a novel growth factor that acts through the ErbB-4 receptor tyrosine kinase. Oncogene, 18: 2681-2689, 1999. 50. Riese, D. J., 2nd, van Raaij, T. M., Plowman, G. D., Andrews, G. C., and Stern, D. F. The cellular response to neuregulins is governed by complex interactions of the erbB receptor family. Mol Cell Biol, 15: 5770-5776, 1995. 51. Zhang, D., Sliwkowski, M. X., Mark, M., Frantz, G., Akita, R., Sun, Y., Hillan, K., Crowley, C., Brush, J., and Godowski, P. J. Neuregulin-3 (NRG3): a novel neural tissue-enriched protein that binds and activates ErbB4. Proc Natl Acad Sci USA, 94: 9562-9567, 1997. 52. Prigent, S. A. and Gullick, W. J. Identification of c-erbB-3 binding sites for phosphatidylinositol 3''-kinase and SHC using an EGF receptor/c-erbB-3 chimera. EMBO J, 13: 2831-2841, 1994. 53. Normanno, N., De Luca, A., Maiello, M. R., Mancino, M., D''Antonio, A., Macaluso, M., Caponigro, F., and Giordano, A. Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors in breast cancer: current status and future development. Front Biosci, 10: 2611-2617, 2005. 54. Sellers, W. R. and Fisher, D. E. Apoptosis and cancer drug targeting. J Clin Invest, 104: 1655-1661, 1999. 55. Weishaupt, J. H., Neusch, C., and Bahr, M. Cyclin-dependent kinase 5 (CDK5) and neuronal cell death. Cell Tissue Res, 312: 1-8, 2003. 56. Dhavan, R. and Tsai, L. H. A decade of CDK5. Nat Rev Mol Cell Biol, 2: 749-759, 2001. 57. Lee, M. S., Kwon, Y. T., Li, M., Peng, J., Friedlander, R. M., and Tsai, L. H. Neurotoxicity induces cleavage of p35 to p25 by calpain. Nature, 405: 360-364, 2000. 58. Ubeda, M., Kemp, D. M., and Habener, J. F. 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, 2004. 59. Lilja, L., Yang, S. N., Webb, D. L., Juntti-Berggren, L., Berggren, P. O., and Bark, C. Cyclin-dependent kinase 5 promotes insulin exocytosis. J Biol Chem, 276: 34199-34205, 2001. 60. Xin, X., Ferraro, F., Back, N., Eipper, B. A., and Mains, R. E. Cdk5 and Trio modulate endocrine cell exocytosis. J Cell Sci, 117: 4739-4748, 2004. 61. Lilja, L., Johansson, J. U., Gromada, J., Mandic, S. A., Fried, G., Berggren, P. O., and Bark, C. Cyclin-dependent kinase 5 associated with p39 promotes Munc18-1 phosphorylation and Ca(2+)-dependent exocytosis. J Biol Chem, 279: 29534-29541, 2004. 62. 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. 63. 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. 64. Zhang, Q., Ahuja, H. S., Zakeri, Z. F., and Wolgemuth, D. J. Cyclin-dependent kinase 5 is associated with apoptotic cell death during development and tissue remodeling. Dev Biol, 183: 222-233, 1997. 65. Grossmann, M. E., Huang, H., and Tindall, D. J. Androgen receptor signaling in androgen-refractory prostate cancer. J Natl Cancer Inst, 93: 1687-1697, 2001. 66. 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. 67. Craft, N., Shostak, Y., Carey, M., and Sawyers, C. L. A mechanism for hormone-independent prostate cancer through modulation of androgen receptor signaling by the HER-2/neu tyrosine kinase. Nat Med, 5: 280-285, 1999. 68. Nazareth, L. V. and Weigel, N. L. Activation of the human androgen receptor through a protein kinase A signaling pathway. J Biol Chem, 271: 19900-19907, 1996. 69. 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. 70. Krauss, W. C., Park, J. W., Kirpotin, D. B., Hong, K., and Benz, C. C. Emerging antibody-based HER2 (ErbB-2/neu) therapeutics. Breast Dis, 11: 113-124, 2000. 71. Kato, S., Endoh, H., Masuhiro, Y., Kitamoto, T., Uchiyama, S., Sasaki, H., Masushige, S., Gotoh, Y., Nishida, E., Kawashima, H., Metzger, D., and Chambon, P. Activation of the estrogen receptor through phosphorylation by mitogen-activated protein kinase. Science, 270: 1491-1494, 1995. 72. Slamon, D. J., Godolphin, W., Jones, L. A., Holt, J. A., Wong, S. G., Keith, D. E., Levin, W. J., Stuart, S. G., Udove, J., Ullrich, A., and et al. Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. Science, 244: 707-712, 1989. 73. Jenster, G., de Ruiter, P. E., van der Korput, H. A., Kuiper, G. G., Trapman, J., and Brinkmann, A. O. Changes in the abundance of androgen receptor isotypes: effects of ligand treatment, glutamine-stretch variation, and mutation of putative phosphorylation sites. Biochemistry, 33: 14064-14072, 1994. 74. Lin, H. K., Yeh, S., Kang, H. Y., and Chang, C. Akt suppresses androgen-induced apoptosis by phosphorylating and inhibiting androgen receptor. Proc Natl Acad Sci USA, 98: 7200-7205, 2001. 75. Wen, Y., Hu, M. C., Makino, K., Spohn, B., Bartholomeusz, G., Yan, D. H., and Hung, M. C. HER-2/neu promotes androgen-independent survival and growth of prostate cancer cells through the Akt pathway. Cancer Res, 60: 6841-6845, 2000. 76. Zhou, Z. X., Kemppainen, J. A., and Wilson, E. M. Identification of three proline-directed phosphorylation sites in the human androgen receptor. Mol Endocrinol, 9: 605-615, 1995. 77. Zhu, Z., Becklin, R. R., Desiderio, D. M., and Dalton, J. T. Identification of a novel phosphorylation site in human androgen receptor by mass spectrometry. Biochem Biophys Res Commun, 284: 836-844, 2001. 78. 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. 79. Gregory, C. W., Whang, Y. E., McCall, W., Fei, X., Liu, Y., Ponguta, L. A., French, F. S., Wilson, E. M., and Earp, H. S. 3rd, Heregulin-induced activation of HER2 and HER3 increases androgen receptor transactivation and CWR-R1 human recurrent prostate cancer cell growth. Clin Cancer Res, 11: 1704-1712, 2005. 80. Carraway, K. L., 3rd, Soltoff, S. P., Diamonti, A. J., and Cantley, L. C. Heregulin stimulates mitogenesis and phosphatidylinositol 3-kinase in mouse fibroblasts transfected with erbB2/neu and erbB3. J Biol Chem, 270: 7111-7116, 1995. 81. Nan, B., Snabboon, T., Unni, E., Yuan, X. J., Whang, Y. E., and Marcelli, M. The PTEN tumor suppressor is a negative modulator of androgen receptor transcriptional activity. J Mol Endocrinol, 31: 169-183, 2003. 82. Lin, H. K., Hu, Y. C., Yang, L., Altuwaijri, S., Chen, Y. T., Kang, H. Y., and Chang, C. Suppression versus induction of androgen receptor functions by the phosphatidylinositol 3-kinase/Akt pathway in prostate cancer LNCaP cells with different passage numbers. J Biol Chem, 278: 50902-50907, 2003. 83. Lin, H. K., Wang, L., Hu, Y. C., Altuwaijri, S., and Chang, C. Phosphorylation-dependent ubiquitylation and degradation of androgen receptor by Akt require Mdm2 E3 ligase. EMBO J, 21: 4037-4048, 2002. 84. Lee, D. K. and Chang, C. Endocrine mechanisms of disease: Expression and degradation of androgen receptor: mechanism and clinical implication. J Clin Endocrinol Metab, 88: 4043-4054, 2003. 85. Wong, H. Y., Burghoorn, J. A., Van Leeuwen, M., De Ruiter, P. E., Schippers, E., Blok, L. J., Li, K. W., Dekker, H. L., De Jong, L., Trapman, J., Grootegoed, J. A., and Brinkmann, A. O. Phosphorylation of androgen receptor isoforms. Biochem J, 383: 267-276, 2004. 86. Lange, C. A., Shen, T., and Horwitz, K. B. Phosphorylation of human progesterone receptors at serine-294 by mitogen-activated protein kinase signals their degradation by the 26S proteasome. Proc Natl Acad Sci USA, 97: 1032-1037, 2000. 87. Nawaz, Z., Lonard, D. M., Dennis, A. P., Smith, C. L., and O''Malley, B. W. Proteasome-dependent degradation of the human estrogen receptor. Proc Natl Acad Sci USA, 96: 1858-1862, 1999. 88. Sheflin, L., Keegan, B., Zhang, W., and Spaulding, S. W. Inhibiting proteasomes in human HepG2 and LNCaP cells increases endogenous androgen receptor levels. Biochem Biophys Res Commun, 276: 144-150, 2000. 89. Lipford, J. R. and Deshaies, R. J. Diverse roles for ubiquitin-dependent proteolysis in transcriptional activation. Nat Cell Biol, 5: 845-850, 2003. 90. Nawaz, Z., Lonard, D. M., Smith, C. L., Lev-Lehman, E., Tsai, S. Y., Tsai, M. J., and O''Malley, B. W. The Angelman syndrome-associated protein, E6-AP, is a coactivator for the nuclear hormone receptor superfamily. Mol Cell Biol, 19: 1182-1189, 1999. 91. Freeman, M. R. HER2/HER3 heterodimers in prostate cancer: Whither HER1/EGFR? Cancer Cell, 6: 427-428, 2004. 92. Chen, F., Wang, Q., Wang, X., and Studzinski, G. P. 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 Res, 64: 5425-5433, 2004. 93. Goodyear, S. and Sharma, M. C. Roscovitine regulates invasive breast cancer cell (MDA-MB231) proliferation and survival through cell cycle regulatory protein cdk5. Exp Mol Pathol, 82: 25-32, 2007. 94. Selvendiran, K., Koga, H., Ueno, T., Yoshida, T., Maeyama, M., Torimura, T., Yano, H., Kojiro, M., and Sata, M. Luteolin promotes degradation in signal transducer and activator of transcription 3 in human hepatoma cells: an implication for the antitumor potential of flavonoids. Cancer Res, 66: 4826-4834, 2006. 95. Kim, E., Chen, F., Wang, C. C., and Harrison, L. E. CDK5 is a novel regulatory protein in PPARgamma ligand-induced antiproliferation. Int J Oncol, 28: 191-194, 2006. 96. 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, 2006. 97. 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. 98. 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. 99. 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. 100. 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. 101. 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. 102. Miyajima, M., Nornes, H. O., and Neuman, T. Cyclin E is expressed in neurons and forms complexes with cdk5. Neuroreport, 6: 1130-1132, 1995. 103. Prevarskaya, N., Skryma, R., and Shuba, Y. Ca2+ homeostasis in apoptotic resistance of prostate cancer cells. Biochem Biophys Res Commun, 322: 1326-1335, 2004. 104. Carafoli, E. Calcium pump of the plasma membrane. Physiol Rev, 71: 129-153, 1991. 105. Gunter, T. E. and Pfeiffer, D. R. Mechanisms by which mitochondria transport calcium. Am J Physiol, 258: C755-786, 1990. 106. Gill, D. L., Ghosh, T. K., and Mullaney, J. M. Calcium signalling mechanisms in endoplasmic reticulum activated by inositol 1,4,5-trisphosphate and GTP. Cell Calcium, 10: 363-374, 1989. 107. Nicotera, P. and Orrenius, S. The role of calcium in apoptosis. Cell Calcium, 23: 173-180, 1998. 108. Fu, A. K., Fu, W. Y., Cheung, J., Tsim, K. W., Ip, F. C., Wang, J. H., and Ip, N. Y. Cdk5 is involved in neuregulin-induced AChR expression at the neuromuscular junction. Nat Neurosci, 4: 374-381, 2001. 109. Fu, A. K., Ip, F. C., Fu, W. Y., Cheung, J., Wang, J. H., Yung, W. H., and Ip, N. Y. Aberrant motor axon projection, acetylcholine receptor clustering, and neurotransmission in cyclin-dependent kinase 5 null mice. Proc Natl Acad Sci USA, 102: 15224-15229, 2005. 110. Li, B. S., Ma, W., Jaffe, H., Zheng, Y., Takahashi, S., Zhang, L., Kulkarni, A. B., and Pant, H. C. Cyclin-dependent kinase-5 is involved in neuregulin-dependent activation of phosphatidylinositol 3-kinase and Akt activity mediating neuronal survival. J Biol Chem, 278: 35702-35709, 2003. 111. Xie, F., Padival, M., and Siegel, R. E. Association of PSD-95 with ErbB4 facilitates neuregulin signaling in cerebellar granule neurons in culture. J Neurochem, 100: 62-72, 2007. 112. Xie, F., Raetzman, L. T., and Siegel, R. E. Neuregulin induces GABAA receptor beta2 subunit expression in cultured rat cerebellar granule neurons by activating multiple signaling pathways. J Neurochem, 90: 1521-1529, 2004. 113. Lin, H., Lin, T. Y., and Juang, J. L. Abl deregulates Cdk5 kinase activity and subcellular localization in Drosophila neurodegeneration. Cell Death Differ, 14: 607-615, 2007. 114. Lin, T. Y., Huang, C. H., Chou, W. G., and Juang, J. L. Abi enhances Abl-mediated CDC2 phosphorylation and inactivation. J Biomed Sci, 11: 902-910, 2004. 115. Tan, M., Jing, T., Lan, K. H., Neal, C. L., Li, P., Lee, S., Fang, D., Nagata, Y., Liu, J., Arlinghaus, R., Hung, M. C., and Yu, D. Phosphorylation on tyrosine-15 of p34(Cdc2) by ErbB2 inhibits p34(Cdc2) activation and is involved in resistance to taxol-induced apoptosis. Mol Cell, 9: 993-1004, 2002. 116. Lee, M. S. and Tsai, L. H. Cdk5 at the junction. Nat Neurosci, 4: 340-342, 2001. 117. 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. 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. Mol Endocrinol, 21: 1552-1568, 2007. 118. 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. 119. Aaronson, D. S., Muller, M., Neves, S. R., Chung, W. C., Jayaram, G., Iyengar, R., and Ram, P. T. An androgen-IL-6-Stat3 autocrine loop re-routes EGF signal in prostate cancer cells. Mol Cell Endocrinol, 270: 50-56, 2007. 120. Lee, S. O., Lou, W., Hou, M., de Miguel, F., Gerber, L., and Gao, A. C. Interleukin-6 promotes androgen-independent growth in LNCaP human prostate cancer cells. Clin Cancer Res, 9: 370-376, 2003. 121. Lee, S. O., Lou, W., Johnson, C. S., Trump, D. L., and Gao, A. C. Interleukin-6 protects LNCaP cells from apoptosis induced by androgen deprivation through the Stat3 pathway. Prostate, 60: 178-186, 2004. 122. Spiotto, M. T. and Chung, T. D. STAT3 mediates IL-6-induced growth inhibition in the human prostate cancer cell line LNCaP. Prostate, 42: 88-98, 2000.
摘要: 
Cyclin-dependent kinase 5 (Cdk5) 蛋白於Cdk家族中屬於獨特的ㄧ員,其並不涉及細胞週期的調控,且激酶活性不需由cyclin蛋白所啟動。近十多年來,Cdk5及其專一活化蛋白p35之功能被熱烈探討於中樞神經系統與神經退化性疾病中。然而,在人類惡性腫瘤方面,Cdk5則是近年來被研究的新興蛋白質。本論文的實驗結果顯示,Cdk5及p35蛋白皆表現於有雄性激素受體(androgen receptor, AR)的LNCaP細胞(人類攝護腺癌細胞株)中。AR是配體依賴核轉錄因子,調控著攝護腺癌細胞之增生。首先利用免疫沉澱法及免疫細胞化學染色法確認Cdk5、p35及AR蛋白間的生化交互作用。在有R1881(人工合成的雄性激素)處理下,過度表現Cdk5或p35蛋白會提高AR蛋白Ser81位置之磷酸化及AR本身蛋白表現。反之,Ser81位置的磷酸化、AR蛋白穩定度及AR蛋白於細胞核內之分佈,則會受到Cdk5活性抑制劑roscovitine (Rv)的處理而被抑制。此外,抑制掉Cdk5活性也會抑制AR下游調控基因,攝護腺特異抗原(PSA)的表現及外泌。而MTT分析的結果也顯示,Cdk5活性調控了LNCaP細胞之增生。在攝護腺癌最新的研究顯示,Her2-ErbB3受體能經由透過下游訊息路徑以增加AR蛋白Ser81的磷酸化,而此路徑已證實並非PI3K/Akt路徑。我們首先利用免疫沉澱法確認Her2-ErbB3受體與Cdk5-p35蛋白間的交互關係。前人的研究顯示,Cdk5蛋白Tyr15位置的磷酸化可用以代表其活性的上升。而在Her2活性抑制劑AG825的處理下,Cdk5蛋白Tyr15的磷酸化及下游AR蛋白穩定度也會受到抑制。反之,生長因子heregulin (HRG)的加入,則可使Her2-ErbB3受體透過Cdk5增加AR蛋白Ser81磷酸化以及攝護腺癌細胞的增生。除了AR蛋白以外,STAT3蛋白也是被廣泛研究的轉錄因子。Cdk5蛋白可與STAT3進行交互作用,並磷酸化STAT3蛋白的Ser727位置。在本實驗室甲狀腺癌的研究發現,Her2受體會透過磷酸化Cdk5激酶Tyr15的位置,進而磷酸化STAT3蛋白。而本論文題目的研究顯示,Her2受體的活性調控了Cdk5與STAT3之間的交互作用,以及STAT3蛋白Ser727位置的磷酸化。綜合以上結果,Her2-Cdk5路徑對於AR和STAT3蛋白功能及攝護腺癌細胞增生的調控扮演了重要的角色,並且為治療攝護腺癌的基礎醫學研究提供了ㄧ個新方向。同時也可能為ErbB受體蛋白在腫瘤生物學上繼乳癌後開啟新的一頁。

Cyclin-dependent kinase 5 (Cdk5) is a unique member of Cdk family without involving cell cycle regulation. The functions of Cdk5 and its neuron-specific activator p35 were extensively explored in both neuronal development and neurodegenerative disease in recent decades. However, the roles of Cdk5 are still unclear in human cancers and need to be further investigated. Our results demonstrated that expression of Cdk5 and p35 protein was present in LNCaP cells (human prostate cancer cell line) which harbored expression of androgen receptor (AR). AR is a ligand-dependent nuclear transcription factor that mediates prostate cancer cell proliferation. The triple complex of Cdk5, AR, and p35 was first identified by immunoprecipitation and immunocytochemistry. Under the treatment of R1881 (synthetic androgen), we found that the levels of phosphorylation of AR Ser81 site and AR protein were increased by overexpression of Cdk5 or p35. In addition, phosphorylation (S81), protein stability and nuclear translocation of AR were all affected by the specific Cdk5 activity inhibitor (roscovitine). Moreover, Cdk5 inhibition decreased both expression and secretion of AR downstream gene, prostate-specific antigen (PSA). The up-to-date research of prostate cancer indicated that Her2-ErbB3 provided signals to regulate AR activation except through PI3k/Akt pathway. The biochemical interactions among Her2-ErbB3 and Cdk5-p35 were first identified by immunoprecipitation. The Tyr15 phosphorylation of Cdk5 was indicated to represent its rising activity. The Tyr15 phosphorylation of Cdk5 and AR protein stability were declined by the specific Her2 activity inhibitor (AG825). In addition to AR, STAT3 was another transcription factor enthusiastically discussed in human cancer cells. Cdk5 was reported to be a kinase corresponding to Ser727 phosphorylation of STAT3. The interaction among STAT3, Cdk5 and p35 was also recognized by immunoprecipitation. The level of STAT3 Ser727 phosphorylation was paralleled to Cdk5 protein expression. Besides, the Her2 activity-dependent interaction between STAT3 and Cdk5 was determined by immunoprecipitation. Furthermore, the HRG-induced LNCaP cell growth was significantly blocked by roscovitine, which indicating that HRG modulated cell growth through Cdk5 activity. Taken together with these results, Her2-ErbB3 might play important roles in regulating AR/STAT3 functions and prostate cancer cell proliferation through Cdk5 activity, and Her2-Cdk5-AR/STAT3 axis might be potential therapeutic targets to prostate cancer.
URI: http://hdl.handle.net/11455/22500
其他識別: U0005-0708200720594200
Appears in Collections:生命科學系所

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