Androgen receptor repression of gonadotropin-releasing hormone gene transcription via enhancer 1

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• 作者：Melissa J. Brayman ; Patricia A. Pepa ; Pamela L. Mellon
• 关键词：cs ; charcoal/dextran-treated ; DBD ; DNA-binding domain ; DHT ; 5¦Á-dihydrotestosterone ; GnRH-E ; GnRH enhancer ; GnRH-P ; GnRH promoter ; HPG ; hypothalamic-pituitary-gonadal ; LBD ; ligand-binding domain ; MMTV ; mouse mammary tumor virus ; Nkx2.1 ; NK2 homeobox 1 ; Oc
• 刊名：Molecular and Cellular Endocrinology
• 出版年：2012
• 出版时间：5 November, 2012
• 年：2012
• 卷：363
• 期：1-2
• 页码：92-99
• 全文大小：845 K

文摘

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.