REGULATION OF ANDROGEN RECEPTOR ACTIVITY IN THE PROSTATE

前列腺雄激素受体活性的调节

• 批准号: 6524272
• 负责人: Michael J. Garabedian
• 金额: $ 29.19万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-08-01 至 2004-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6524272
• 关键词: androgen receptor; cell growth regulation; hormone regulation /control mechanism; nucleic acid probes; prostate; protein protein interaction; tissue /cell culture; transcription factor; transfection; yeast two hybrid system

DESCRIPTION (Adapted from the application) Our broad, long term objective is to characterize the molecular mechanisms by which the androgen receptor (AR) regulates transcriptional activation through its N-terminus. The AR is a hormone- dependent transcription factor involved in the regulation of both normal and malignant prostate cell growth. Although androgen hormones, such as dihydrotestosterone (DHT), act as the primary signal in activating AR's transcriptional regulatory functions, AR-mediated transcriptional activity is also controlled by associations with, as yet, unidentified regulatory cofactors involved in transcription. The N-terminus of AR contain several transcriptional activation functions, including AF-1a and AF-1b, and mutations in these domains reduce AR-dependent transcriptional activity. We propose that these domains provide surfaces that permit protein-protein contacts between the AR N-terminus and cofactors involved in transcriptional regulation. We propose that these domains provide surfaces that permit protein-protein contacts between the AR N-terminus and cofactors involved in transcriptional regulation. We will identify proteins that interact with the AR N-terminal activation domains using a modified yeast two-hybrid approach that is capable. Of isolating proteins that interact with transcriptional activators.. We will also define the effect of these AR-interact with transcriptional activators. We will also define the effect of these AR-interacting proteins on AR- transcriptional activity using a transient transfection proteins on AR- transcriptional activity using a transient transfection system designed to monitor AR-dependent transcriptional activation in cultured mammalian cells. Conceivably, alterations in the level of these AR N-terminal interacting proteins modulate AR activity., thereby, contributing to malignant AR-dependent prostate growth if altered in cancer. To test this hypothesis we will determine if the concentration of specific AR- interacting proteins varies in models of benign and malignant prostate growth using antibody and nucleic acid probes. Understanding of the communication between AR and the proteins that associate with the AR N-terminal transcriptional activation domain is fundamental to understanding the mechanism of AR-regulated gene expression and may reveal novel points of intervention to be exploited in the development of new therapies for AR-dependent malignancies, such as prostate cancer.

描述（改编自申请）我们广泛的长期目标是表征雄激素受体 (AR) 通过其 N 末端调节转录激活的分子机制。 AR是一种激素依赖性转录因子，参与正常和恶性前列腺细胞生长的调节。尽管雄激素，如二氢睾酮 (DHT)，是激活 AR 转录调节功能的主要信号，但 AR 介导的转录活性也受到与转录相关的尚未识别的调节辅因子的关联控制。 AR 的 N 末端包含多种转录激活功能，包括 AF-1a 和 AF-1b，这些结构域中的突变会降低 AR 依赖性转录活性。 我们认为这些结构域提供了允许 AR N 末端和参与转录调控的辅助因子之间蛋白质-蛋白质接触的表面。我们认为这些结构域提供了允许 AR N 末端和参与转录调控的辅助因子之间蛋白质-蛋白质接触的表面。我们将使用一种改良的酵母双杂交方法来鉴定与 AR N 端激活结构域相互作用的蛋白质。分离与转录激活剂相互作用的蛋白质。我们还将定义这些 AR 与转录激活剂相互作用的效果。我们还将使用瞬时转染蛋白来定义这些 AR 相互作用蛋白对 AR 转录活性的影响，使用瞬时转染系统来监测培养的哺乳动物细胞中 AR 依赖性转录激活。 可以想象，这些 AR N 端相互作用蛋白水平的改变会调节 AR 活性，因此，如果在癌症中发生改变，则会导致恶性 AR 依赖性前列腺生长。为了检验这一假设，我们将使用抗体和核酸探针确定良性和恶性前列腺生长模型中特定 AR 相互作用蛋白的浓度是否变化。了解 AR 和与 AR N 端转录激活结构域相关的蛋白质之间的通讯对于理解 AR 调节基因表达的机制至关重要，并且可能揭示在开发 AR 新疗法中可利用的新干预点依赖性恶性肿瘤，例如前列腺癌。