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

The androgen receptor (AR) is a ligand-dependent transcription activator re sponsible 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 (A R122) to the Kruppel-associated box (KRAB) repressor domain and/or histone deacetylase (HDAC1). The HDAC1-KRAB-AR122 protein was the most successful d ominant negative AR, capable of repressing the wild type AR ninefold when c o-expressed at a 1:1 plasmid ratio. A maximal repression of 41-fold was ach ieved 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-depen dent 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 triggerin g repression by HDAC1-KRAB-AR122. The potent dominant negative AR proteins might prove useful tools to inhibit AR function in vitro and in vivo. (C) 2 001 Elsevier Science Ireland Ltd. All rights reserved.