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

Nathalie Bruck1, Dominique Vitoux, Christine Ferry

  • 1Department 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.

The EMBO Journal
|December 17, 2008
PubMed

Insights

Retinoic acid (RA) signaling in cancer cells is controlled by a novel phosphorylation cascade. This pathway, initiated by p38MAPK/MSK1, is essential for RA receptor alpha (RARalpha) target gene activation.

Area of Science:

  • Molecular Biology
  • Cell Signaling
  • Cancer Research

Background:

  • Nuclear retinoic acid receptor alpha (RARalpha) regulates gene expression via ligand-dependent interactions with coregulators.
  • Understanding RARalpha target gene regulation is crucial for cancer therapy.

Purpose of the Study:

  • To elucidate a novel mechanism controlling RARalpha target gene transcription.
  • To investigate the role of phosphorylation cascades in RA signaling.

Main Methods:

  • Investigated the p38MAPK/MSK1 pathway activation by RA.
  • Analyzed MSK1-mediated phosphorylation of RARalpha at S369.
  • Examined TFIIH binding and N-terminal domain phosphorylation by cdk7/cyclin H.
  • Assessed histone H3 phosphorylation at S10.
  • Studied the recruitment of RARalpha/TFIIH complexes to response elements.

Main Results:

  • RA rapidly activates the p38MAPK/MSK1 pathway.
  • MSK1 phosphorylates RARalpha at S369, facilitating TFIIH binding and subsequent N-terminal phosphorylation.
  • MSK1 also phosphorylates histone H3 at S10.
  • This phosphorylation cascade is critical for RARalpha/TFIIH complex recruitment and target gene activation.
  • Cancer cells with deregulated p38MAPK/MSK1 pathways are unresponsive to RA.

Conclusions:

  • A novel RA-triggered phosphorylation cascade controls RARalpha target gene transcription.
  • The p38MAPK/MSK1 pathway and subsequent phosphorylations are essential for RA signaling.
  • Dysregulation of this cascade contributes to RA resistance in cancer cells.

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