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AR Suppresses Transcription of the Glycoprotein Hormone Subunit Gene Through Protein-Protein Interactions with cJun and Activation Transcription Factor 2

Department of Pharmacology, Case Western Reserve University, Cleveland, Ohio 44106-4965

Address all correspondence and requests for reprints to: Dr. John Nilson, Department of Pharmacology, Case Western Reserve University School of Medicine, W319, 2109 Adelbert Road, Cleveland, Ohio 44106-4965.

Previously, we reported that the AR directly suppressed transcription of the glycoprotein hormone subunit (GSU) gene in a ligand-dependent fashion while ER had no effect. Mutagenesis studies of the GSU promoter indicated that two elements were required for AR-mediated suppression: the basal element and tandem cAMP response elements (CREs). Because several members of the bZip family of transcriptional proteins can bind the CREs, we used several functional assays to determine whether AR interacts selectively with cJun, activation transcription factor 2 (ATF2), or CRE binding protein (CREB). When tested by cotransfection with AR, cJun and ATF2 specifically rescued androgen-mediated suppression of the GSU-reporter construct in a gonadotrope-derived cell line. In contrast, cotransfected CREB displayed no activity in this rescue assay. In fact, overexpression of CREB alone diminished activity of the GSU promoter, suggesting that the transcriptional activity normally conferred by the tandem CREs in gonadotropes requires their occupancy by cJun/ATF2 heterodimers. Binding assays carried out with a glutathione-S-transferase-AR fusion protein indicated that the receptor itself also displayed a clear preference for binding cJun and ATF2. Furthermore, we ruled out the possibility that AR suppressed activity of the GSU promoter by reducing synthesis of these bZip proteins. Additional experiments suggested that phosphorylation of AR or histone acetylation are unlikely requirements for AR suppression of GSU promoter activity. Thus, our data suggest that AR suppresses activity of the GSU promoter through direct protein-protein interactions with cJun and ATF2.

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