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A coordinated phosphorylation cascade initiated by MSK1 directs RAR alpha recruitment to target gene promoters

Nathalie Bruck¹, Dominique Vitoux², Christine Ferry¹, Vanessa Duong¹, Annie Bauer¹, Hughes de The³ & Cecile Rochette-Egly¹

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1. IGBMC, Functional genomics, Strasbourg, France
2. CNRS UMR 7151, Hopital saint Louis, Paris, France
3. CNRS UMR 7151, Centre Hayem, Paris, France

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Document Type:

Manuscript

Date:

Received 22 July 2008 17:03 UTC; Posted 23 July 2008

Subjects:

Molecular Cell Biology

Tags:

• transcription
• Retinoic acid receptors
• MSK1
• phosphorylation

Abstract:

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 is required for the recruitment of RARα/TFIIH complexes to response elements and subsequently for RARα target genes 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 signaling.

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This document is licensed to the public under the Creative Commons Attribution 3.0 License

How to cite this document:

Bruck, Nathalie, Vitoux, Dominique, Ferry, Christine, Duong, Vanessa, Bauer, Annie, de The, Hughes, and Rochette-Egly, Cecile. A coordinated phosphorylation cascade initiated by MSK1 directs RAR alpha recruitment to target gene promoters. Available from Nature Precedings <http://hdl.handle.net/10101/npre.2008.2107.1> (2008)

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