A coordinated phosphorylation cascade initiated by p38MAPK/MSK1 directs RARalpha to target promoters.
The nuclear retinoic acid (RA) receptor alpha (RARalpha) is a transcriptional transregulator that controls the expression of specific gene subsets through binding at response elements and dynamic interactions with coregulators, which are coordinated by the ligand. Here, we highlighted a novel paradigm in which the transcription of RARalpha target genes is controlled by phosphorylation cascades initiated by the rapid RA activation of the p38MAPK/MSK1 pathway. We demonstrate that MSK1 phosphorylates RARalpha at S369 located in the ligand-binding domain, allowing the binding of TFIIH and thereby phosphorylation of the N-terminal domain at S77 by cdk7/cyclin H. MSK1 also phosphorylates histone H3 at S10. Finally, the phosphorylation cascade initiated by MSK1 controls the recruitment of RARalpha/TFIIH complexes to response elements and subsequently RARalpha target gene activation. Cancer cells characterized by a deregulated p38MAPK/MSK1 pathway, do not respond to RA, outlining the essential contribution of the RA-triggered phosphorylation cascade in RA signalling.
Bruck
Nathalie
N
Department of Functional Genomics, Institut de Génétique et de Biologie Moléculaire et Cellulaire, INSERM U596, CNRS UMR7104, Université Louis Pasteur de Strasbourg, CU de Strasbourg, France.
Vitoux
Dominique
D
Ferry
Christine
C
Duong
Vanessa
V
Bauer
Annie
A
de Thé
Hughes
H
Rochette-Egly
Cécile
C
D000818:Animals; D002460:Cell Line; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D005786:Gene Expression Regulation; D006657:Histones / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D018168:Receptors, Retinoic Acid / Q000378:metabolism*; D000072482:Retinoic Acid Receptor alpha; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000378:metabolism*; D051758:Transcription Factor TFIIH / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
D018844:Cyclin-Dependent Kinases; D006657:Histones; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; D038744:Ribosomal Protein S6 Kinases, 90-kDa; D051758:Transcription Factor TFIIH; D048051:p38 Mitogen-Activated Protein Kinases; C000607072:Rara protein, mouse; C116919:mitogen and stress-activated protein kinase 1; C090586:Cdk7 protein, mouse