The amino terminus of the human AR is target for corepressor action and antihormone agonism

Molecular Endocrinology
Helmut DotzlawAria Baniahmad

Abstract

Antiandrogens inhibit the ligand-induced transactivation by the androgen receptor (AR) and have a widespread use in the treatment of prostate cancer but their mode of action is not fully understood. Here we show that the ability of the antiandrogen cyproterone acetate (CPA) to inhibit transactivation by the human AR (hAR) involves the corepressor SMRT (silencing mediator for retinoic acid and thyroid hormone receptor). We detect binding of SMRT to hAR when treating with the antiandrogen CPA, but not with the antihormones casodex or hydroxyflutamide. Interestingly, we find that SMRT binds to the N terminus of the hAR. Thereby, SMRT modulates the activity of hAR in receptor-negative CV1 cells. In addition, we have used receptor point mutants that exhibit normal transactivation potential and unchanged partial agonistic activity when treated with CPA, but lack both SMRT binding and SMRT-mediated inhibition of CPA-bound AR. This indicates that mechanisms involved in hAR-mediated transactivation are distinct from antihormone-induced receptor inactivation. Furthermore, we show that treatment of transfected cells with a cAMP analog or coexpression of the catalytic subunit of PKA, known to activate hAR, inhibits the binding of SMRT to t...Continue Reading

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Citations

Mar 16, 2004·Proceedings of the National Academy of Sciences of the United States of America·Chih-Cheng TsaiRonald M Evans
Jul 5, 2005·Proceedings of the National Academy of Sciences of the United States of America·Yuexing ZhangAnne W Hamburger
Apr 17, 2003·Proceedings of the National Academy of Sciences of the United States of America·C J LoyE L Yong
Aug 18, 2006·Molecular and Cellular Biology·Yin WuRyoichi Takayanagi
Oct 15, 2008·Molecular Cancer Therapeutics·Myles C HodgsonSteven P Balk
Jan 20, 2004·Molecular and Cellular Biology·Yanqing ZhangChawnshang Chang
Dec 2, 2004·Molecular and Cellular Biology·Ding-Yen LinHsiu-Ming Shih
Sep 19, 2008·Human Mutation·Jean-Pierre Bergerat, Jocelyn Céraline
Nov 14, 2015·Journal of Molecular Neuroscience : MN·Aria Baniahmad
Apr 30, 2005·The Journal of Steroid Biochemistry and Molecular Biology·Aria Baniahmad
Jan 18, 2006·Biochemical and Biophysical Research Communications·Shuli FanToshihiko Yanase
Aug 14, 2012·Neurobiology of Disease·Marija CvetanovicPuneet Opal
Mar 26, 2013·Toxicology in Vitro : an International Journal Published in Association with BIBRA·Lenka PaskovaZdenek Kolar
Jul 26, 2011·Molecular and Cellular Endocrinology·Andreas GrosseAria Baniahmad
Sep 24, 2013·Molecular and Cellular Endocrinology·Christine Helsen, Frank Claessens
Dec 14, 2006·International Journal of Cancer. Journal International Du Cancer·Renée ChmelarNorman M Greenberg
Jun 19, 2013·International Journal of Molecular Sciences·Nada LallousPaul S Rennie
Jan 5, 2008·Nuclear Receptor Signaling·Maria PapaioannouAria Baniahmad
Oct 16, 2004·The Prostate·Liang WangChawnshang Chang
Jun 10, 2014·Acta Pharmacologica Sinica·Mh Eileen TanEu-Leong Yong
Jun 7, 2003·Molecular Endocrinology·Christoph GeserickBernard Haendler
Mar 16, 2007·Molecular Endocrinology·Udo MoehrenAria Baniahmad

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