Premium
A coordinated phosphorylation cascade initiated by p38MAPK/MSK1 directs RARα to target promoters
Author(s) -
Bruck Nathalie,
Vitoux Dominique,
Ferry Christine,
Duong Vanessa,
Bauer Annie,
de Thé Hughes,
RochetteEgly Cécile
Publication year - 2009
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1038/emboj.2008.256
Subject(s) - biology , phosphorylation , promoter , cascade , microbiology and biotechnology , genetics , computational biology , gene , gene expression , chemistry , chromatography
The nuclear retinoic acid (RA) receptor alpha (RARα) 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 RARα target genes is controlled by phosphorylation cascades initiated by the rapid RA activation of the p38MAPK/MSK1 pathway. We demonstrate that MSK1 phosphorylates RARα 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 RARα/TFIIH complexes to response elements and subsequently RARα 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.