Role of PIASy in Androgen Signaling and Prostate Cancer

描述(申请人提供)：雄激素信号的异常激活 通路在前列腺癌的发生和发展中发挥核心作用 进步。控制雄激素依赖基因的分子细节 前列腺癌中的激活以及雄激素受体的作用 特别是，抑制者在很大程度上仍未得到开发。我们的实验室有 确定了一系列蛋白质作为STAT(信号转导和信号转导)的抑制因子 转录激活子)信号转导被命名为PIAS(蛋白抑制因子 激活状态)。我们的初步结果显示，PIAS的一名成员 PIASy家族是雄激素信号的有效抑制因子。PIASy绑定到 雄激素受体(AR)的DNA结合域，但不影响 AR与DNA结合的能力。我们还证明了PIASy在人类中表达 前列腺癌和PIASy水平随着 在某些前列腺癌异种移植中进展为雄激素非依赖性。这个 这项建议的总体目标是研究PIASY的分子基础 对雄激素信号的抑制作用，并探索假设 作为一种AR抑制因子，PIASy的下调参与了 雄激素非依赖性前列腺癌的生长。拟议的研究将是 在柯帅博士的实验室进行，并由 查尔斯·索耶斯博士都在加州大学洛杉矶分校工作。这个 列出的实验将使应聘者在以下方面获得严格的培训 分子生物学技术，并将这些知识用于理解 前列腺癌。应聘者还注册了分子生物学专业 加州大学洛杉矶分校的跨部门博士课程，预计将完成 第一年对分子生物学博士学位的要求 这项提议。作为一名肿瘤内科医生，候选人S的职业目标是 结合信号转导和肿瘤生物学领域的研究 了解和治疗前列腺癌。

DESCRIPTION (provided by applicant): Aberrant activation of the androgen-signaling pathway plays a central role in prostate cancer development and progression. The molecular details controlling androgen-dependent gene activation in prostate cancer, in general, and the role of androgen receptor repressors, in particular, remain largely unexplored. Our laboratory has identified a family of proteins as inhibitors of STAT (signal transducer and activator of transcription) signaling named PIAS (protein inhibitor of activated STAT). Our preliminary results show that one member of the PIAS family, PIASy, is a potent repressor of androgen signaling. PIASy binds to the DNA binding domain of androgen receptor (AR), but does not affect the ability of AR to bind to DNA. We also show that PIASy is expressed in human prostate cancer and that the level of PIASy is decreased along with progression to androgen-independence in some prostate cancer xenografts. The overall goals of this proposal are to study the molecular basis of the PIASy inhibitory effect on androgen signaling and explore the hypothesis that down regulation of PIASy, as an AR repressor, is involved in the progression to androgen-independent prostate cancer growth. The proposed research will be performed at the laboratory of Dr. Ke Shuai under the additional guidance of Dr. Charles Sawyers both at the University of California at Los Angeles. The experiments outlined will enable the candidate to obtain rigorous training in molecular biology techniques and apply this knowledge towards understanding prostate cancer. The candidate is also enrolled in the Molecular Biology Interdepartmental doctoral program at UCLA and is expected to complete the requirements for a doctorate in molecular biology during the first year of this proposal. As a medical oncologist, the candidate?s career goal is to combine research in the fields of signal transduction and tumor biology to understand and treat prostate cancer.