Androgenic Inactivation of FKHR in Prostate Cancer

前列腺癌中 FKHR 的雄激素失活

• 批准号: 6897791
• 负责人: DONALD J. TINDALL
• 金额: $ 25.55万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-08-01 至 2007-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6897791
• 关键词: androgens; apoptosis; benign prostate hyperplasia; cell growth regulation; cytotoxicity; endopeptidases; hormone regulation /control mechanism; mass spectrometry; prostate neoplasms; protein purification; protein sequence; protein structure function; proteolysis; site directed mutagenesis; tissue /cell culture; transcription factor

DESCRIPTION (provided by applicant): Benign prostate hyperplasia (BPH) and prostate cancer are two major health problems of men in this country. The androgen receptor is critical for both growth and survival of benign and cancerous prostate cells. Mitogenic effects of androgens are mediated in part by androgen-induced increases in proliferation-promoting proteins, such as proliferating cell nuclear antigen (PCNA), cyclin-dependent kinases 2 and 4, as well as decreases in cell cycle inhibitors, such as cyclin-dependent kinase inhibitor p16 ink4a. Although the mechanistic details of the anti-apoptotic effects of androgens are far from elucidated, progress has been made recently in our laboratory and others. We and others have demonstrated that androgens act as survival factors by antagonizing the function of the tumor suppressor gene PTEN. An effector downstream of PTEN, the forkhead transcription factor FKHR, plays a critical role in apoptosis by inducing the transcription of proapoptotic genes. We and others have shown that forced expression of FKHR induces apoptosis in prostate cancer cells, suggesting that FKHR is a critical pro-apoptotic player in prostate cancer cells. Our data have demonstrated that androgens abrogate FKHR-induced death of prostate cancer cells. Moreover, we have demonstrated that androgens inhibit the activity of FKHR by regulating lysosome-mediated proteolysis of this protein. Thus, we hypothesize that androgens antagonize death of prostate cells at least in part via their inhibitory effects on the pro-apoptotic function of FKHR. To test this hypothesis, we propose to (1) determine the proteolytic cleavage site in the FKHR protein; (2) identify the androgen-regulated protease(s) that cleaves FKHR; (3) determine whether blockage of the effect of androgens on FKHR favors the death of prostate cancer cells. These findings should enhance our understanding of the action of androgens on growth and survival of both normal and malignant prostate cells. Also, identification of such novel proteins will enable us to better manipulate androgen-regulated events in BPH and prostate cancer.

描述（由申请人提供）：