Androgen Receptor Regulation by Phosphorylation

通过磷酸化调节雄激素受体

• 批准号: 7511884
• 负责人: Shaoyong Chen
• 金额: $ 9.73万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-01 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7511884
• 关键词: Active Sites; Androgen Receptor; Androgens; Binding; Biological; Biological Process; CDC2 Protein Kinase; Cancer Relapse; Catalytic Domain; Cells; Chromatin; DNA Binding Domain; Data; Development; Glucocorticoid Receptor; Goals; Lead; Malignant Neoplasms; Malignant neoplasm of prostate; Mentors; Mitosis; Normal tissue morphology; Nuclear Translocation; Phase; Phosphoric Monoester Hydrolases; Phosphorylation; Phosphotransferases; Play; Progesterone; Protein Dephosphorylation; Protein phosphatase; Recruitment Activity; Regulation; Reporting; Role; Site; Steroid Receptors; Steroids; cancer cell; deprivation; insight; novel strategies; receptor; receptor function; response; steroid hormone receptor

DESCRIPTION (provided by applicant): The androgen receptor (AR) plays a central role in prostate cancer (PCa) development and progression, and appears to adapt to low levels of androgens in PCa that relapses after androgen deprivation therapy. More effective targeting of AR will require a better understanding of how its expression, stability, and activity are regulated. The AR is phosphorylated at multiple sites, and data from many groups indicate that several kinases can modulate AR activity, but it is not yet clear whether these kinases directly target AR. Moreover, it is not known how phosphorylation at specific sites regulates AR activity. As detailed in a recent report, we found that Cdk1 is an AR kinase and can enhance AR stability and responses to low levels of androgen. Our Preliminary Data further indicate that a biological function of Cdk1 may be to stabilize AR during the G2/M phase of the cell cyle. However, we do not yet know whether, or by what mechanisms, AR phosphorylation by Cdk1 regulates AR stability or functions. Therefore, my overall goals during the mentored phase of this proposal are to identify the sites on AR that are phosphorylated by Cdk1 and to determine the biological significance of phosphorylation at these sites (Aim 1). My Preliminary Studies also demonstrate that AR interacts with the catalytic subunit of protein phosphatase 1 (PP1), and that PP1 can stabilize AR and markedly enhance its transcriptional activity. Significantly, it is not yet clear whether AR is a substrate for PP1, or whether AR functions as a regulatory subunit for PP1 (which may target PP1 to chromatin and/or modulate its phosphatase activity). Moreover, the Preliminary Studies also indicate that other steroid hormone receptors similarly interact with PP1. During the mentored phase of this proposal I will initiate studies to determine whether AR is a PP1 substrate and to identify the specific sites on AR that are dephosphorylated by PP1 (Aim 2a). During the independent phase I will determine the biological function of AR phosphorylation/dephosphorylation at any identified PP1 target sites (Aim 2b) and will further explore the hypothesis that AR and other steroid receptors function to target PP1 to chromatin (Aim 3). These studies will provide new insight into how the activities of AR and other steroid receptors are regulated, and lead to new approaches for regulating these activities in steroid dependent normal tissues and cancers.

描述（由申请人提供）：雄激素受体（AR）在前列腺癌（PCA）发育和进展中起着核心作用，并且似乎适应了PCA中低水平的雄激素，从而在雄激素剥夺治疗后复发。更有效的AR靶向将需要更好地了解其表达，稳定性和活动的调节。 AR在多个位点被磷酸化，许多组的数据表明几种激酶可以调节AR活性，但尚不清楚这些激酶是否直接靶向AR。此外，尚不清楚在特定位点的磷酸化如何调节AR活性。正如最近的一份报告中所详述的那样，我们发现CDK1是AR激酶，可以增强AR稳定性和对低水平雄激素的反应。我们的初步数据进一步表明，CDK1的生物学功能可能是在细胞箱的G2/m期稳定AR。但是，我们尚不知道CDK1的AR磷酸化是否或通过哪种机制来调节AR稳定性或功能。因此，我在该提案的指导阶段的总体目标是确定AR上由CDK1磷酸化的位点，并确定这些位点磷酸化的生物学意义（AIM 1）。我的初步研究还表明，AR与蛋白质磷酸酶1（PP1）的催化亚基相互作用，并且PP1可以稳定AR并显着增强其转录活性。值得注意的是，尚不清楚AR是PP1的底物，还是AR作为PP1的调节亚基（可能针对PP1靶向染色质和/或调节其磷酸酶活性）。此外，初步研究还表明，其他类固醇激素受体与PP1相似。在该提案的指导阶段，我将启动研究，以确定AR是否为PP1底物，并确定AR上由PP1去磷酸化的特定位点（AIM 2A）。在独立阶段，I将在任何已鉴定的PP1靶位点（AIM 2B）确定AR磷酸化/去磷酸化的生物学功能，并将进一步探讨AR和其他类固醇受体对靶向PP1靶向染色质的假设（AIM 3）。 这些研究将为如何调节AR和其他类固醇受体的活性提供新的见解，并为调节类固醇依赖的正常组织和癌症的新方法提供了新的方法。