Nuclear receptor corepressor (NCoR) mediates transcriptional repression by unliganded nuclear receptors and certain steroid hormone receptors (SHRs) bound to nonphysiological antagonists, but has not been found to regulate SHRs bound to their natural ligands. This report demonstrates that NCoR interacts directly with the androgen receptor (AR) and represses dihydrotestosterone-stimulated AR transcriptional activity. The NCoR C terminus, containing the receptor interacting domains, was necessary for repression, which was ablated by mutations in the corepressor nuclear receptor (CoRNR) boxes. In contrast, the NCoR N terminus, containing domains that can recruit histone deacetylases, was not necessary for repression. Binding studies in vitro with a series of glutathione-S-transferase-NCoR and -AR fusion proteins demonstrated a direct interaction that was similarly dependent upon the NCoR corepressor nuclear receptor boxes and AR ligand binding domain and was independent of ligand and helix 12 in the AR ligand binding domain. This NCoR-AR interaction was further demonstrated in mammalian two-hybrid assays and by coimmunoprecipitation of the endogenous proteins from a prostate cancer cell line. Finally, AR transcriptional activity could be enhanced in vivo by sequestration of endogenous NCoR with unliganded thyroid hormone receptor. These results demonstrate that AR, in contrast to other SHRs, is regulated by NCoR and suggest the possibility of developing selective AR modulators that enhance this interaction.
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