Transcription activating and repressing functions of the androgen receptorare differentially influenced by mutations in the deoxyribonucleic acid-binding domain

Despite the wide spectrum of androgen receptor (AR) mutants described in an drogen insensitivity syndromes (AIS), their influence on transactivating an d, in particular, transrepressing functions of AR are poorly defined. Rat A R mutants with substitutions in the DNA-binding domain, corresponding to se veral mutations in AIS patients, were examined for these activities. AR var iants (G551V and C562G) with mutations in the first zinc finger (ZF) exhibi ted reduced DNA-binding activity and attenuated transactivation. An R590Q s ubstitution in the second ZF diminished transcriptional activity only from a promoter with a single androgen response element, whereas activation at m ultiple androgen response element sites was unaffected, despite the poor DN A-binding affinity of R590Q. Another substitution in the second ZF, A579T, yielded similar findings. In comparison to wild-type AR, G551V, and C562G v ariants had markedly reduced ability to repress an NF-kappa B/RelA-activate d promoter but R590Q behaved like the native receptor. AP1 function was rep ressed not only by wild-type AR but also by the transactivating mutants A57 9T and R590Q as well as by the transcriptionally inactive mutants G551V and C562G. Furthermore, a Lys-to-Ala substitution in codon 563 of the first ZF switched AR into a ligand-dependent activator at AP1 sites but maintained the ability to repress NF-kappa B/RelA function. Taken together, DNA-bindin g domain mutations in AIS patients influence transcriptional activating and repressing functions of AR in a selective fashion, which probably contribu tes to the complexity in the presentation of the AIS phenotype.