Distinct roles of the steroid receptor coactivator 1 and of MED1 in retinoid-induced transcription and cellular differentiation.
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 retinoid-induced transcription is poorly characterized in vivo. Embryonal carcinoma P19 cells, which are highly sensitive 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 RARbeta2 promoter, and favored a higher RNA polymerase II detection in transcribed regions of the RARbeta2 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.
Flajollet
Sébastien
S
INSERM U459, FacultédeMédecine Henri Warembourg, Lille F-59045, France.
Lefebvre
Bruno
B
Rachez
Christophe
C
Lefebvre
Philippe
P
D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects*; D045744:Cell Line, Tumor; D003001:Cloning, Molecular; D004706:Endodeoxyribonucleases / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D017353:Gene Deletion; D017930:Genes, Reporter; D006367:HeLa Cells; D051548:Histone Acetyltransferases; D006801:Humans; D007700:Kinetics; D008156:Luciferases / Q000235:genetics; D051379:Mice; D008954:Models, Biological; D056920:Nuclear Receptor Coactivator 1; D018168:Receptors, Retinoic Acid / Q000187:drug effects / Q000502:physiology; D012176:Retinoids / Q000494:pharmacology*; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D014158:Transcription, Genetic / Q000187:drug effects*
D018168:Receptors, Retinoic Acid; D012176:Retinoids; D014157:Transcription Factors; D008156:Luciferases; D051548:Histone Acetyltransferases; C538859:NCOA1 protein, human; C538861:Ncoa1 protein, mouse; D056920:Nuclear Receptor Coactivator 1; D004706:Endodeoxyribonucleases; C118712:MBD4 protein, human