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Transcriptional Repression of the -Subunit Gene by Androgen Receptor Occurs Independently of DNA Binding but Requires the DNA-Binding and Ligand-Binding Domains of the Receptor

Department of Molecular and Integrative Physiology (L.L.H.), The University of Kansas Medical Center, Kansas City, Kansas 66160,
The Laboratories for Reproductive Biology (E.M.W.), The University of North Carolina, Chapel Hill, North Carolina 27599-7500,
Department of Pharmacology (J.H.N.), School of Medicine, Case Western Reserve University, Cleveland, Ohio 44106

The pituitary glycoprotein hormones LH and FSH regulate the reproductive cycle and are sensitive to feedback by gonadal steroids. The common -subunit shared by these hormones is transcriptionally repressed by androgen receptor (AR) in the presence of its ligand dihydrotestosterone. This identifies at least one mechanism that contributes to AR-dependent suppression of gonadotropin synthesis. Repression of -subunit transcription by AR requires only the sequences within the first 480 bp of the promoter. While this region contains a high-affinity binding site for AR, this element does not mediate the suppressive effects of androgens. Instead, two other elements within the promoter-regulatory region (-basal element and cAMP-regulatory element), which are important for expression of the -subunit gene in gonadotropes, mediate the effects of AR. This suggests that AR inhibits activity of the -subunit promoter by interfering with the transcriptional properties of the proteins that bind to -basal element and the cAMP-regulatory elements. Furthermore, transfection analysis of various mutant ARs identified both the DNA-binding and ligand-binding domains of the receptor as critical for repression. Comparisons with the MMTV promoter revealed distinct structural requirements that underlie the transactivation and transrepression properties of AR.

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