title: Agonist-antagonist induced coactivator and corepressor interplay on the human androgen receptor.
abstract: The human androgen receptor (AR) is a member of the nuclear hormone receptor superfamily. However, in contrast to other members of this family the amino-(N)-terminus of AR harbors the major transactivation function. Previously we have shown that hormone antagonists that bind to the carboxy-terminal ligand-binding domain repress AR through recruitment of corepressors that are recruited to the receptor N-terminus. Here we show by a modified mammalian two-hybrid system that both the AR interacting domains of the coactivator SRC1 and of the corepressor SMRT compete for interaction with the AR N-terminus. In contrast to other members of the nuclear receptor superfamily the LXXLL motifs of SRC1e are not required for this interaction, instead a stretch of 135 amino acids of the glutamine rich region (Qr) of SRC1e is essential to bind to the AR N-terminus. We show that the Qr-region of SRC1 is able to inhibit the interaction of SMRT with AR. Also, we demonstrate that the corepressor mediated repression decreases the antagonist-induced transactivation while, surprisingly, it increases the agonist-induced transactivation. This may indicate that coactivators and corepressors act in concert to dictate the overall receptor-mediated action dependent on the type of ligand.
authors.affiliation: Genetic Institute, Justus-Liebig-University, Heinrich-Buff-Ring 58-62, D-35392 Giessen, Germany.
authors.forename: Helmut
authors.initials: H
authors.lastname: Dotzlaw
authors.forename: Maria
authors.initials: M
authors.lastname: Papaioannou
authors.forename: Udo
authors.initials: U
authors.lastname: Moehren
authors.forename: Frank
authors.initials: F
authors.lastname: Claessens
authors.forename: Aria
authors.initials: A
authors.lastname: Baniahmad
mesh_terms: D059002:Androgen Receptor Antagonists; D000728:Androgens; D001667:Binding, Competitive; D017373:Cyproterone Acetate / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000378:metabolism / Q000502:physiology; D051548:Histone Acetyltransferases; D006801:Humans; D008024:Ligands; D056985:Nuclear Receptor Co-Repressor 2; D056920:Nuclear Receptor Coactivator 1; D011485:Protein Binding / Q000187:drug effects; D025941:Protein Interaction Mapping; D011944:Receptors, Androgen / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism* / Q000502:physiology; D015534:Trans-Activators / Q000378:metabolism* / Q000502:physiology; D014157:Transcription Factors / Q000378:metabolism / Q000502:physiology
chemical_list: D059002:Androgen Receptor Antagonists; D000728:Androgens; D004268:DNA-Binding Proteins; D008024:Ligands; C539130:NCOR2 protein, human; D056985:Nuclear Receptor Co-Repressor 2; D011944:Receptors, Androgen; D012097:Repressor Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D017373:Cyproterone Acetate; D051548:Histone Acetyltransferases; C538859:NCOA1 protein, human; D056920:Nuclear Receptor Coactivator 1