REGULATION OF ANDROGEN RECEPTOR ACTIVITY IN THE PROSTATE

描述（根据申请改编）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是参与调节正常和恶性前列腺细胞生长的激素依赖性转录因子。虽然雄激素，如双氢睾酮（DHT），作为激活AR的转录调节功能的主要信号，AR介导的转录活性也控制协会，迄今为止，未确定的参与转录的调节辅因子。AR的N-末端包含几种转录激活功能，包括AF-1a和AF-1b，这些结构域中的突变降低了AR依赖的转录活性。 我们建议，这些结构域提供的表面，允许蛋白质-蛋白质之间的AR N-末端和参与转录调控的辅因子的接触。我们建议，这些结构域提供的表面，允许蛋白质-蛋白质之间的AR N-末端和参与转录调控的辅因子的接触。我们将确定与AR N-末端激活结构域相互作用的蛋白质，使用修改后的酵母双杂交方法，能够。分离与转录激活因子相互作用的蛋白质。我们还将确定这些AR与转录激活因子相互作用的效果。我们还将使用瞬时转染系统确定这些AR相互作用蛋白对AR转录活性的影响，所述瞬时转染系统设计用于监测培养的哺乳动物细胞中的AR依赖性转录激活。 可以想象，这些AR N-末端相互作用蛋白水平的改变调节AR活性。因此，如果在癌症中改变，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特定AR相互作用蛋白的浓度在良性和恶性前列腺生长模型中是否变化。了解AR和与AR N-末端转录激活结构域相关的蛋白质之间的通信对于理解AR调节基因表达的机制是至关重要的，并且可以揭示在开发AR依赖性恶性肿瘤（例如前列腺癌）的新疗法中要利用的新的干预点。

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.