A coordinated phosphorylation cascade initiated by p38MAPK/MSK1 directs RARalpha to target promoters. - Archive ouverte HAL Access content directly
Journal Articles EMBO Journal Year : 2009

A coordinated phosphorylation cascade initiated by p38MAPK/MSK1 directs RARalpha to target promoters.

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Abstract

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.

Dates and versions

inserm-00357399 , version 1 (30-01-2009)

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Nathalie Bruck, Dominique Vitoux, Christine Ferry, Vanessa Duong, Annie Bauer, et al.. A coordinated phosphorylation cascade initiated by p38MAPK/MSK1 directs RARalpha to target promoters.. EMBO Journal, 2009, 28 (1), pp.34-47. ⟨10.1038/emboj.2008.256⟩. ⟨inserm-00357399⟩
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