Role of SRCAP in AR-Mediated Transcription

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DESCRIPTION (provided by applicant): Transcriptional activation is a complex process requiring the coordinated action of many proteins. Nuclear receptors form part of a family of ligand-dependent transcription factors that regulate the expression of many genes. The androgen receptor (AR) is a member of this family and it mediates androgen signaling for development, growth, and function of the male reproductive system. Recently many cofactors implicated in the transcriptional activation by nuclear receptors have been identified. These include cofactors that alter chromatin structure and/or facilitate recruitment of RNA polymerase II to the promoters of target genes. SRCAP (SNF2-Related CBP Activator Protein) is a 350 KD protein characterized by a conserved ATPase domain found in the SNF2 family of proteins which function in various aspects of transcriptional regulation. SRCAP was identified in a yeast two-hybrid assay as a protein that binds the coactivator CBP, and it enhances the ability of CBP to activate transcription. We have previously demonstrated in our laboratory that SRCAP functions as a coactivator for CREB and glucocorticoid receptor (GR)-mediated transcription. SRCAP enhances GR transcriptional activation in part by interacting with the p160 coactivator GRIP 1 and the histone methyl transferase CARM1. SRCAP also strongly activates AR-mediated transcription, and exhibits synergistic function for this activation. The objectives of this study are to understand the role of SRCAP in AR-mediated transcription. Since AR function plays a key role in the development and progression of prostate cancer, it is important to understand how coactivator proteins affect its activity.