A coordinated phosphorylation cascade initiated by p38MAPK/MSK1 directs RAR[alpha] 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 paradi...

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Published in:The EMBO journal 2009-01, Vol.28 (1), p.34
Main Authors: Bruck, Nathalie, Vitoux, Dominique, Ferry, Christine, Duong, Vanessa, Bauer, Annie, De Thé, Hughes, Rochette-egly, Cécile
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Language:English
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Binding sites
Cancer
Cellular biology
Gene expression
Molecular biology
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container_title The EMBO journal
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creator Bruck, Nathalie
Vitoux, Dominique
Ferry, Christine
Duong, Vanessa
Bauer, Annie
De Thé, Hughes
Rochette-egly, Cécile
description 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. [PUBLICATION ABSTRACT]
doi_str_mv 10.1038/emboj.2008.256
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subjects Binding sites
Cancer
Cellular biology
Gene expression
Molecular biology
title A coordinated phosphorylation cascade initiated by p38MAPK/MSK1 directs RAR[alpha] to target promoters
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