Repression of androgen-regulated gene expression by dominant negative androgen receptors

Molecular and Cellular Endocrinology
K S BramlettG Jenster

Abstract

The androgen receptor (AR) is a ligand-dependent transcription activator responsible for male sexual development. In order to specifically inhibit the AR pathway, dominant negative ARs were constructed by inactivation of the major transactivation domains of the wild type AR and fusing this mutant (AR122) to the Krüppel-associated box (KRAB) repressor domain and/or histone deacetylase (HDAC1). The HDAC1-KRAB-AR122 protein was the most successful dominant negative AR, capable of repressing the wild type AR ninefold when co-expressed at a 1:1 plasmid ratio. A maximal repression of 41-fold was achieved when HDAC1-KRAB-AR122 was cotransfected with the wild type AR at a 4:1 plasmid ratio. HDAC1-KRAB-AR122 repressed transcription in a ligand-dependent manner since it inhibited a constitutively active AR mutant (AR5) only in the presence of agonists. High concentrations of partial agonists such as RU486, cyproterone acetate, and estradiol were also capable of triggering repression by HDAC1-KRAB-AR122. The potent dominant negative AR proteins might prove useful tools to inhibit AR function in vitro and in vivo.

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Citations

Sep 17, 2005·Clinical Advances in Hematology & Oncology : H&O·Andrew J Armstrong, Michael A Carducci
Apr 22, 2009·BioEssays : News and Reviews in Molecular, Cellular and Developmental Biology·John A CoplandSpiros A Vlahopoulos
Aug 12, 2009·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Sheng-Han WangPei-Jer Chen
Nov 10, 2005·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Howard I Scher, Charles L Sawyers
Nov 27, 2015·Biology of Reproduction·Corey ToocheckWilliam H Walker
Mar 25, 2006·Future Oncology·Iris E EderHelmut Klocker

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