REGULATION OF ANDROGEN RECEPTOR ACTIVITY IN THE PROSTATE

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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.