Action of Hormones on Protein and RNA Metabolism

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The androgen receptor plays a critical role in the development of the male phenotype and in the regulation of homeostatic processes, such as spermatogenesis. In addition, alteration of androgen receptor function have been implicated in the pathogenesis and progression of a number of disease states, including spinal bulbar muscular atrophy and prostate cancer. A large body of experimental work has defined the functional domains of the androgen receptor and identified a number of structural lesion that contribute to alterations of androgen receptor function. The present application seeks to build upon this foundation to identify the proteins that mediate the function of the androgen receptor in controlling gene expression. Three specific aims are proposed: 1) Extension of prior work that has identified two proteins (RFG/ELE1/ARA70 and 23-3) that interact with the ligand- bound androgen receptor. Experiments are outlined to define the genesis and location of potential isoforms and the roles that each plays in the normal function of the human AR. Experiments to produce and characterize mice with conditional disruptions of the RFG/ELE1/ARA70 gene are proposed. 2) Characterization of proteins that have been identified on the basis of their ability to interact with the androgen receptor protein in two-hybrid screens using the intact AR-A to screen a randomly primed cDNA library. 3) Biochemical characterization of proteins that associate with the androgen receptor using a novel immuno purification method to purify native AR expressed in mammalian cells. Extensions of these studies are proposed to permit an analysis of the effects that thee type of ligand, nature of the cell fraction used, and mutations of the AR have on the formation and stability of these complexes. It is anticipated that as a result of these studies a clearer picture will emerge of the proteins that are required for the normal function of the human AR. It is anticipated that this information will have implications for the understanding of androgen resistance syndromes, and for other diseases in which androgens play a pathogenic role, such as benign prostatic hyperplasia and prostate cancer.