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  • The EMBO Journal (2009) 28, 34 - 47
  • doi:10.1038/emboj.2008.256

Published online: 11 December 2008

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

Nathalie Bruck1, Dominique Vitoux2, Christine Ferry1, Vanessa Duong1, Annie Bauer1, Hughes de Thé2 and Cécile Rochette-Egly1

  1. 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
  2. Pathologie et Virologie Moléculaire, CNRS/Université de Paris 7, UMR 7151, Equipe labellisée de la Ligue contre le Cancer, Hôpital Saint Louis, Paris, France

Correspondence to:

Cécile Rochette-Egly, Department of Functional Genomics, Institut de Génétique et de Biologie Moléculaire et Cellulaire, INSERM U596, CNRS UMR7104, Université Louis Pasteur de Strasbourg, BP 10142, 1 rue Laurent Fries, Illkirch Cedex, CU de Strasbourg 67404, France. Tel.: +33 388 65 3459; Fax: +33 388 65 3201; E-mail: cegly@igbmc.fr

Received 10 August 2008; Accepted 11 November 2008

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.

  • Keywords:

    • MSK1,
    • nuclear receptor,
    • phosphorylation,
    • retinoic acid,
    • transcription