Role of PIASy in Androgen Signaling and Prostate Cancer

描述（由申请人提供）：雄激素信号传导的异常激活 在前列腺癌的发展中起着核心作用， 进展雄激素依赖基因的分子调控 前列腺癌中的激活，以及雄激素受体的作用 特别是阻遏物，在很大程度上仍未被探索。本实验室 鉴定了一个蛋白质家族作为STAT（信号转导和 转录激活因子）信号传导，称为皮亚斯（蛋白抑制剂 激活STAT）。我们的初步结果表明，一个成员的皮亚斯， PIASy家族是雄激素信号传导的有效阻遏物。PIASy结合至 雄激素受体（AR）的DNA结合域，但不影响 AR与DNA结合的能力。我们还发现PIASy在人的神经细胞中表达， 前列腺癌和PIASy的水平下降沿着 在某些前列腺癌异种移植物中进展为雄激素非依赖性。的 该提案的总体目标是研究PIASy的分子基础 雄激素信号传导的抑制作用，并探讨这一假设， PIASy作为AR阻遏物的下调参与了向AR的进展。 雄激素非依赖性前列腺癌的生长。拟议的研究将是 在Ke Shuai博士的实验室进行， 博士查尔斯·索耶，都在洛杉矶的加州大学。的 概述的实验将使候选人获得严格的培训， 分子生物学技术，并将这些知识应用于理解 前列腺癌该候选人还参加了分子生物学 跨部门的博士课程在加州大学洛杉矶分校，预计将完成 在第一年的分子生物学博士学位的要求 这个提议。作为一个肿瘤学家，候选人？的职业目标是 联合收割机在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.