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

EMBO J. 2009 Jan 7;28(1):34-47. doi: 10.1038/emboj.2008.256. Epub 2008 Dec 11.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • Cyclin-Dependent Kinases / metabolism
  • Gene Expression Regulation*
  • Histones / metabolism
  • Mice
  • Models, Biological
  • Phosphorylation
  • Promoter Regions, Genetic*
  • Protein Binding
  • Receptors, Retinoic Acid / metabolism*
  • Retinoic Acid Receptor alpha
  • Ribosomal Protein S6 Kinases, 90-kDa / metabolism*
  • Transcription Factor TFIIH / metabolism
  • p38 Mitogen-Activated Protein Kinases / metabolism*

Substances

  • Histones
  • Rara protein, mouse
  • Receptors, Retinoic Acid
  • Retinoic Acid Receptor alpha
  • Transcription Factor TFIIH
  • Ribosomal Protein S6 Kinases, 90-kDa
  • mitogen and stress-activated protein kinase 1
  • Cyclin-Dependent Kinases
  • cyclin-dependent kinase 7, mouse
  • p38 Mitogen-Activated Protein Kinases