Ligand-dependent formation of retinoid receptors, receptor-interacting protein 140 (RIP140), and histone deacetylase complex is mediated by a novel receptor-interacting motif of RIP140.
Receptor-interacting protein 140 (RIP140) interacts with retinoic acid receptor and retinoid X receptor in a ligand-dependent manner and suppresses retinoic acid (RA) induction of its target genes. The receptor-interacting motif is mapped to a C-terminal peptide sequence (LTKTNPILYYMLQK) of RIP140. The functional role of this motif in mediating the suppressive effects of RIP140 on RA induction is demonstrated in mutation studies. RA induces coimmunoprecipitation of histone deacetylase 3 with retinoic acid receptor/retinoid X receptor in the presence of wild type RIP140, but not in the presence of the C-terminal motif-deleted RIP140. A decrease in histone acetylation on the promoter region that carries a RA response element is associated with the expression of wild type RIP140, but not with expression of the mutant RIP140, in a dose-dependent manner. These data provide a molecular explanation for RIP140 acting as a novel ligand-dependent, negative modulator of RA-regulated gene expression.
Department of Pharmacology, University of Minnesota Medical School, Minneapolis, Minnesota 55455, USA. weixx009@tc.umn.edu
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D000107:Acetylation; D048868:Adaptor Proteins, Signal Transducing; D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D019556:COS Cells; D002522:Chlorocebus aethiops; D002843:Chromatin / Q000378:metabolism; D006655:Histone Deacetylases / Q000378:metabolism*; D008969:Molecular Sequence Data; D016296:Mutagenesis; D009687:Nuclear Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D000078723:Nuclear Receptor Interacting Protein 1; D011401:Promoter Regions, Genetic; D018168:Receptors, Retinoic Acid / Q000378:metabolism*; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism*; D047488:Retinoid X Receptors; D017384:Sequence Deletion; D014157:Transcription Factors / Q000378:metabolism; D014162:Transfection; D014212:Tretinoin / Q000494:pharmacology*
D048868:Adaptor Proteins, Signal Transducing; D002843:Chromatin; D009687:Nuclear Proteins; D000078723:Nuclear Receptor Interacting Protein 1; D018168:Receptors, Retinoic Acid; D011994:Recombinant Proteins; D012097:Repressor Proteins; D047488:Retinoid X Receptors; D014157:Transcription Factors; D014212:Tretinoin; D006655:Histone Deacetylases