Distinct Roles of the Steroid Receptor Coactivator 1 and of MED1 in Retinoid-induced Transcription and Cellular Differentiation

Sébastien Flajollet, Bruno Lefebvre, Christophe Rachez, Philippe Lefebvre
2006 Journal of Biological Chemistry  
Retinoic acid receptors (RARs) are the molecular relays of retinoid action on transcription, cellular differentiation and apoptosis. Transcriptional activation of retinoid-regulated promoters requires the dismissal of corepressors and the recruitment of coactivators to promoter-bound RAR. RARs recruit in vitro a plethora of coactivators whose actual contribution to retinoidinduced transcription is poorly characterized in vivo. Embryonal carcinoma P19 cells, which are highly sensitive to
more » ... ensitive to retinoids, were depleted from archetypical coactivators by RNAi. SRC1-deficient P19 cells showed severely compromised retinoid-induced responses, in agreement with the supposed role of SRC1 as a RAR coactivator. Unexpectedly, Med1/TRAP220/DRIP205-depleted cells exhibited an exacerbated response to retinoids, both in terms transcriptional responses and of cellular differentiation. Med1 depletion affected TFIIH and cdk9 detection at the prototypical retinoid-regulated RAR␤2 promoter, and favored a higher RNA polymerase II detection in transcribed regions of the RAR␤2 gene. Furthermore, the nature of the ligand impacted strongly on the ability of RARs to interact with a given coactivator and to activate transcription in intact cells. Thus RAR accomplishes transcriptional activation as a function of the ligand structure, by recruiting regulatory complexes which control distinct molecular events at retinoid-regulated promoters. Coactivators (CoAs) 5 have multiple roles in transcriptional regulation: they are key structural components of multiprotein complexes, notably by interacting with transactivating domains
doi:10.1074/jbc.m603023200 pmid:16723356 fatcat:lta6uv2foreu3okiidmvu2zmo4