title: The corepressor CTBP2 is a coactivator of retinoic acid receptor/retinoid X receptor in retinoic acid signaling.
abstract: Retinoids play key roles in development, differentiation, and homeostasis through regulation of specific target genes by the retinoic acid receptor/retinoid X receptor (RAR/RXR) nuclear receptor complex. Corepressors and coactivators contribute to its transcriptional control by creating the appropriate chromatin environment, but the precise composition of these nuclear receptor complexes remains to be elucidated. Using an RNA interference-based genetic screen in mouse F9 cells, we identified the transcriptional corepressor CTBP2 (C-terminal binding protein 2) as a coactivator critically required for retinoic acid (RA)-induced transcription. CTBP2 suppression by RNA interference confers resistance to RA-induced differentiation in diverse murine and human cells. Mechanistically, we find that CTBP2 associates with RAR/RXR at RA target gene promoters and is essential for their transactivation in response to RA. We show that CTBP2 is indispensable to create a chromatin environment conducive for RAR/RXR-mediated transcription by recruiting the histone acetyltransferase p300. Our data reveal an unexpected function of the corepressor CTBP2 as a coactivator for RAR/RXR in RA signaling.
authors.affiliation: Divisions of Molecular Carcinogenesis, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: Prashanth Kumar
authors.initials: PK
authors.lastname: Bajpe
authors.forename: Guus J J E
authors.initials: GJ
authors.lastname: Heynen
authors.forename: Lorenza
authors.initials: L
authors.lastname: Mittempergher
authors.forename: Wipawadee
authors.initials: W
authors.lastname: Grernrum
authors.forename: Iris A
authors.initials: IA
authors.lastname: de Rink
authors.forename: Wouter
authors.initials: W
authors.lastname: Nijkamp
authors.forename: Roderick L
authors.initials: RL
authors.lastname: Beijersbergen
authors.forename: Rene
authors.initials: R
authors.lastname: Bernards
authors.forename: Sidong
authors.initials: S
authors.lastname: Huang
mesh_terms: D000429:Alcohol Oxidoreductases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002454:Cell Differentiation; D002460:Cell Line; D045744:Cell Line, Tumor; D056970:Co-Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D051379:Mice; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D034622:RNA Interference; D018168:Receptors, Retinoic Acid / Q000378:metabolism*; D047488:Retinoid X Receptors / Q000378:metabolism*; D015398:Signal Transduction; D014158:Transcription, Genetic; D014212:Tretinoin / Q000378:metabolism*; D050880:p300-CBP Transcription Factors / Q000378:metabolism; D000099224:p300-CBP-Associated Factor
chemical_list: D000429:Alcohol Oxidoreductases; D056970:Co-Repressor Proteins; D004268:DNA-Binding Proteins; D009419:Nerve Tissue Proteins; D010750:Phosphoproteins; D018168:Receptors, Retinoic Acid; D047488:Retinoid X Receptors; D014212:Tretinoin; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor; C421248:CTBP2 protein, human; C111341:Ctbp2 protein, mouse