Role of PIASy in Androgen Signaling and Prostate Cancer

PIASy 在雄激素信号传导和前列腺癌中的作用

• 批准号: 7095944
• 负责人: MITCHELL E GROSS
• 金额: $ 12.36万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-08-21 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7095944
• 关键词: DNA binding protein; androgen receptor; biological signal transduction; cell line; gene induction /repression; genetic regulation; molecular oncology; neoplasm /cancer genetics; neoplastic process; oncoproteins; pathologic process; prostate neoplasms; protein binding; protein structure function

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.

描述（由申请人提供）：雄激素信号传导异常激活 途径在前列腺癌的发生和发展中发挥着核心作用 进展。控制雄激素依赖性基因的分子细节 一般来说，前列腺癌中的激活以及雄激素受体的作用 尤其是抑制因子，在很大程度上仍未得到探索。我们实验室有 确定了一个蛋白质家族作为 STAT（信号转导和 转录激活剂）信号传导称为 PIAS（转录激活剂）信号传导 激活 STAT）。我们的初步结果表明 PIAS 的一名成员 PIASy 家族是雄激素信号传导的有效抑制因子。 PIASy 结合 雄激素受体（AR）的DNA结合域，但不影响 AR与DNA结合的能力。我们还表明 PIASy 在人类中表达 前列腺癌并且 PIASy 水平随着 一些前列腺癌异种移植物进展为雄激素非依赖性。这 该提案的总体目标是研究 PIASy 的分子基础 对雄激素信号传导的抑制作用并探索以下假设： PIASy 作为 AR 阻遏物的下调参与了 不依赖雄激素的前列腺癌生长。拟议的研究将是 在柯帅博士实验室的额外指导下进行 查尔斯·索耶斯 (Charles Sawyers) 博士均来自加州大学洛杉矶分校。这 概述的实验将使候选人能够获得严格的培训 分子生物学技术并应用这些知识来理解 前列腺癌。该候选人还注册了分子生物学 加州大学洛杉矶分校跨部门博士课程，预计完成 分子生物学博士学位第一年的要求 这个建议。作为一名肿瘤内科医生，候选人的职业目标是 结合信号转导和肿瘤生物学领域的研究 了解并治疗前列腺癌。