title: Androgen receptor repression of gonadotropin-releasing hormone gene transcription via enhancer 1.
abstract: Gonadotropin-releasing hormone (GnRH) plays a major role in the hypothalamic-pituitary-gonadal (HPG) axis, and synthesis and secretion of GnRH are regulated by gonadal steroid hormones. Disruptions in androgen levels are involved in a number of reproductive defects, including hypogonadotropic hypogonadism and polycystic ovarian syndrome. Androgens down-regulate GnRH mRNA synthesis in vivo and in vitro via an androgen receptor (AR)-dependent mechanism. Methyltrienolone (R1881), a synthetic AR agonist, represses GnRH expression through multiple sites in the proximal promoter. In this study, we show AR also represses GnRH transcription via the major enhancer (GnRH-E1). A multimer of the -1800/-1766 region was repressed by R1881 treatment. Mutation of two bases, -1792 and -1791, resulted in decreased basal activity and a loss of AR-mediated repression. AR bound to the -1796/-1791 sequence in electrophoretic mobility shift assays, indicating a direct interaction with DNA or other transcription factors in this region. We conclude that AR repression of GnRH-E1 acts via multiple AR-responsive regions, including the site at -1792/-1791.
authors.affiliation: Department of Reproductive Medicine and the Center for Reproductive Science and Medicine, University of California, San Diego, La Jolla, CA 92093-0674, USA.
authors.forename: Melissa J
authors.initials: MJ
authors.lastname: Brayman
authors.forename: Patricia A
authors.initials: PA
authors.lastname: Pepa
authors.forename: Pamela L
authors.initials: PL
authors.lastname: Mellon
mesh_terms: D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D002460:Cell Line; D047369:Chromatin Immunoprecipitation; D015536:Down-Regulation; D004742:Enhancer Elements, Genetic; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D007987:Gonadotropin-Releasing Hormone / Q000235:genetics / Q000378:metabolism*; D008156:Luciferases / Q000096:biosynthesis / Q000235:genetics; D015741:Metribolone / Q000494:pharmacology; D051379:Mice; D008969:Molecular Sequence Data; D011485:Protein Binding; D011944:Receptors, Androgen / Q000502:physiology*; D017422:Sequence Analysis, DNA; D045165:Testosterone Congeners / Q000494:pharmacology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014158:Transcription, Genetic
chemical_list: D011944:Receptors, Androgen; D045165:Testosterone Congeners; D015741:Metribolone; D007987:Gonadotropin-Releasing Hormone; D008156:Luciferases; D013755:Tetradecanoylphorbol Acetate