Androgen receptor (AR) is a hormone-regulated transcription factor that mediates a wide array of biological processes including sexual differentiation, spermatogenesis, and prostate cancer progression. The transcriptional activity of AR and other members of the nuclear receptor superfamily are modulated by coregulatory proteins. In this study, we have investigated the regulation of AR transcriptional activity by the silencing mediator for retinoid and thyroid hormone receptors (SMRT). We found that AR possesses an intrinsic transcriptional repression activity, and AR interacts directly with SMRT. One interacting surface on AR is mapped to the ligand-binding domain, and the presence of a DNA binding/hinge region enhances this interaction. The binding surface on SMRT is mapped to the C-terminal ID2 region, and mutation in the ID2 corepressor motif inhibits the interaction. Overexpression of SMRT inhibits dihydrotestosterone-dependent transactivation by AR and further suppresses the antiandrogen flutamide-mediated inhibition of AR activity. We provide evidence to suggest that the mechanisms of SMRT-mediated inhibition of AR activity involves inhibition of AR N/C interaction and competition with the p160 coactivator. Our data establish a significant role of SMRT in modulating AR transcriptional activity.
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