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Transcriptional Regulation of the Androgen Receptor Cofactor Androgen Receptor Trapped Clone-27

Departments of Microbiology (J.C.N., W.L., I.P.-T., M.J.G.), Pharmacology (J.C.N., R.R., S.K.L.), and Urology (H.Y.H., R.R., E.S., S.S.T., S.K.L., M.J.G.), New York University Cancer Institute, New York University (NYU) School of Medicine, New York, New York 10016

Address all correspondence and requests for reprints to: Michael J. Garabedian, Department of Microbiology, 550 First Avenue, New York, New York 10016. E-mail: garabm01{at}med.nyu.edu.

Cofactors modulate nuclear receptor activity and impact human health and disease, yet surprisingly little is known about their transcriptional regulation. Androgen receptor trapped clone-27 (ART-27) is a cofactor that binds to androgen receptor (AR) amino terminus and modulates AR-dependent transcription. Interestingly, ART-27 displays both a cell type- and developmental stage-specific expression pattern. However, the cis-acting elements and trans-acting factors affecting ART-27 gene expression have not been elucidated. We found that ART-27 gene expression is repressed and its promoter is histone H3-K27 tri-methylated in human embryonic kidney cells, but not prostate cells, and the histone deacetylase inhibitor, trichostatin A, relieves this inhibition. The DNA response elements that control the induction of ART-27 gene expression were also characterized. The major cis-acting element corresponds to a consensus cAMP-responsive element (CRE) and binds the CRE-binding protein (CREB) as shown by EMSA and chromatin immunoprecipitation assays. Furthermore, ART-27 promoter activity is induced upon CREB overexpression. Epidermal growth factor, which activates CREB via phosphorylation, also induces ART-27 expression, whereas a reduction in CREB phosphorylation or expression blocks this induction in prostate cells. In human prostate development, both epithelial and stromal cells express CREB; however, active phosphorylated CREB is restricted to epithelial cells where ART-27 is expressed. Based on these findings, we propose a transcriptional regulatory circuit for the developmental expression of ART-27 that includes repression by chromatin modification through a trichostatin A-sensitive factor and activation upon growth factor stimulation via CREB.

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Coregulators:   ART-27