Androgen Receptor Associated Proteins in Prostate Cancer

前列腺癌中雄激素受体相关蛋白

• 批准号: 6864918
• 负责人: ZIJIE SUN
• 金额: $ 27.09万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-07-23 至 2008-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6864918
• 关键词: SDS polyacrylamide gel electrophoresis; androgen receptor; androgens; biological signal transduction; cadherins; cell line; cell proliferation; clinical research; flow cytometry; gene targeting; genetic transcription; genetically modified animals; immunocytochemistry; laboratory mouse; male; molecular oncology; northern blottings; prostate neoplasms; protein protein interaction; tissue /cell culture; transcription factor; transfection

DESCRIPTION (provided by applicant): Like most cancers, prostate carcinogenesis involves a multistep progression from precancerous cells to cells that proliferate locally in an unregulated fashion and then metastasize. Observations from androgen ablation treatment of prostate cancer have shown that the androgen-signaling pathway is important for the growth and progression of prostate cancer. The growth-promoting effects of androgen are mediated mostly through the androgen receptor (AR). AR is a member of the nuclear hormone receptor family and plays a central role in the development of the normal prostate and in prostate cancer through the regulation of ligand dependent transcription. Understanding the mechanisms by which the AR regulates gene expression should, therefore, provide insight into abnormalities that may contribute to the development of prostate cancer and provide possible targets for future treatment. In the past four years, we and others have demonstrated that the function of AR is regulated by other transcriptional activators, repressors, and modulators. In particular, we recently identified three important, but distinct, AR-interacting proteins, which include a transcriptional activator, beta-catenin; a transcriptional repressor, TGIF; and a novel transcription factor, TAC10. Recent studies have shown that both beta-catenin and TGIF play critical roles in normal development and tumorigenesis through the Wnt and TGF-beta signaling pathways, respectively. TAC10 is a protein that was identified by a modified yeast one-hybrid system. It is selectively expressed in prostate cells and contains a potent transactivation domain. Based on this evidence, we hypothesize that these three factors are critical mediators in androgen signaling in prostate cells, and that their regulation or dysregulation are important in the pathogenesis of prostate cancer. Therefore, we propose several approaches to study the mechanisms by which these cofactors regulate AR action and to define the biological significance of these interactions in the development and progression of prostate cancer. The Specific Aims are as follows: (1) Examine the interaction between AR and beta-catenin in prostate cancer cells; (2) Determine how TGIF regulates AR activity in prostate cancer cells; (3) Study the biological roles of TAC 10 in modulating AR-mediated transcription.

描述（由申请人提供）：与大多数癌症一样，前列腺致癌作用涉及从癌前细胞到细胞的多阶段进展，这些细胞以不受管制的方式在局部增殖，然后转移。雄激素消融治疗前列腺癌的观察表明，雄激素信号途径对于前列腺癌的生长和进展至关重要。雄激素的生长促进作用主要是通过雄激素受体（AR）介导的。 AR是核激素受体家族的成员，通过调节配体依赖性转录在正常前列腺和前列腺癌中起着核心作用。因此，了解AR调节基因表达的机制应提供对可能有助于前列腺癌发展的异常的见解，并为将来的治疗提供了可能的靶标。在过去的四年中，我们和其他人表明，AR的功能受其他转录激活因子，阻遏物和调节剂的调节。特别是，我们最近确定了三种重要但独特的AR互动蛋白，其中包括转录激活剂Beta-catenin。转录阻遏物TGIF；和一种新颖的转录因子TAC10。最近的研究表明，β-catenin和TGIF分别通过WNT和TGF-β信号通路在正常发育和肿瘤发生中起关键作用。 TAC10是一种通过改良的酵母单杂交系统鉴定的蛋白质。它在前列腺细胞中有选择性表达，并包含一个有效的反式激活结构域。根据这一证据，我们假设这三个因素是前列腺细胞中雄激素信号传导的关键介体，并且它们的调节或失调对前列腺癌的发病机理很重要。因此，我们提出了几种研究这些辅助因子调节AR作用并定义这些相互作用在前列腺癌发展和进展中的生物学意义的机制的方法。具体目的如下：（1）检查前列腺癌细胞中AR和β-catenin之间的相互作用； （2）确定TGIF如何调节前列腺癌细胞中的AR活性； （3）研究TAC 10在调节AR介导的转录中的生物学作用。