Suppressive effect of receptor-interacting protein 140 on coregulator binding to retinoic acid receptor complexes, histone-modifying enzyme activity, and gene activation.
Gene induction by retinoic acid (RA) is suppressed by overexpression of receptor-interacting protein 140 (RIP140). RIP140-mediated suppression was reversed most effectively by overexpressing the coactivator p300/CREB-binding protein-associated factor (P/CAF). Immunoprecipitation demonstrated coexistence of holoreceptors complexed with RIP140 or P/CAF. Chromatin immunoprecipitation revealed rapid RA-enhanced recruitment of RIP140, but delayed P/CAF recruitment, to an RA-targeted promoter in COS-1 cells supplemented with RIP140. In RA-induced P19 cells, endogenous RIP140 was rapidly (within 4 h) and significantly recruited to both the RARbeta2 and TR2 genes, whereas the peak of endogenous P/CAF recruitment occurred much later (48 h) and to a lesser degree. Consistent with these observations, significant histone acetylation of endogenous RA receptor (RAR) targets was only observed 48 h following RA treatment. In vitro experiments confirmed RA-induced transcription from a chromatin template, which was reduced by adding RIP140. This study presents evidence for coexistence of multiple RAR-coregulator complexes and a preferential RA-induced recruitment of RIP140 to endogenous RAR-targeted promoters after short term RA treatment, which correlates with suppressed induction of RA-regulated gene expression in the presence of RIP140.
Department of Pharmacology, University of Minnesota Medical School, Minneapolis, Minnesota 55455, USA.
Xinli
X
Hu
Yixin
Y
Chen
Mariya
M
Farooqui
Mary C
MC
Thomas
Cheng-Ming
CM
Chiang
Li-Na
LN
Wei
D000123:Acetyltransferases / Q000378:metabolism*; D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D019556:COS Cells; D018797:Cell Cycle Proteins / Q000378:metabolism*; D002522:Chlorocebus aethiops; D005786:Gene Expression Regulation / Q000187:drug effects; D051548:Histone Acetyltransferases; D007700:Kinetics; D009687:Nuclear Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D000078723:Nuclear Receptor Interacting Protein 1; D018168:Receptors, Retinoic Acid / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D014157:Transcription Factors; D015533:Transcriptional Activation; D014162:Transfection; D014212:Tretinoin / Q000494:pharmacology*; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor
D000123:Acetyltransferases; D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; D051548:Histone Acetyltransferases; D009687:Nuclear Proteins; D000078723:Nuclear Receptor Interacting Protein 1; D018168:Receptors, Retinoic Acid; D011994:Recombinant Proteins; D014157:Transcription Factors; D014212:Tretinoin; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor