Agonist–antagonist induced coactivator and corepressor interplay on the human androgen receptor

• Published in: Molecular and cellular endocrinology 2003-12, Vol.213 (1), p.79-85
• Main Authors: Dotzlaw, Helmut, Papaioannou, Maria, Moehren, Udo, Claessens, Frank, Baniahmad, Aria
• Format: Article
• Language: English
• Subjects: Androgen Receptor Antagonists; Androgens; Binding, Competitive; Coactivators and corepressors on androgen receptor; Cofactor recruitment; Cyproterone Acetate - pharmacology; DNA-Binding Proteins - metabolism; DNA-Binding Proteins - physiology; Histone Acetyltransferases; Humans; Ligand; Ligands; Nuclear Receptor Co-Repressor 2; Nuclear Receptor Coactivator 1; Protein Binding - drug effects; Protein Interaction Mapping; Receptors, Androgen - metabolism; Repressor Proteins - metabolism; Repressor Proteins - physiology; Trans-Activators - metabolism; Trans-Activators - physiology; Transcription Factors - metabolism; Transcription Factors - physiology
• ISSN: 0303-7207; 1872-8057
• DOI: 10.1016/j.mce.2003.10.036

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.