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MSK1 triggers the expression of the INK4AB/ARF locus in oncogene-induced senescence

Raphaël Culerrier1, Maëlle Carraz2, Carl Mann3

  • 1Université de Toulouse, UPS, LBCMCP, CNRS, F-31062 Toulouse, France.

Molecular Biology of the Cell
|July 8, 2016
PubMed

Insights

Mitogen- and stress-activated kinase (MSK1) activates tumor suppressor genes p15(INK4B) and p16(INK4A) during oncogenic stress. MSK1-mediated histone phosphorylation drives gene expression, crucial for cellular senescence.

Area of Science:

  • Cellular Biology
  • Epigenetics
  • Molecular Oncology

Background:

  • The INK4AB/ARF locus, encoding tumor suppressors p15(INK4B), p16(INK4A), and p14(ARF), regulates cellular senescence.
  • This locus is epigenetically silenced by Polycomb complexes but activates under oncogenic stress.

Purpose of the Study:

  • To investigate the role of mitogen- and stress-activated kinase (MSK1) in the transcriptional activation of the INK4AB/ARF locus during oncogene-induced senescence.
  • To elucidate the mechanism by which MSK1 regulates histone modifications and gene expression at this locus.

Main Methods:

  • Analysis of MSK1 expression and localization in response to RAF1 oncogenic stress.
  • Chromatin immunoprecipitation (ChIP) to assess histone modifications (H3S28ph, H3K27me3) at the INK4AB/ARF locus.
  • MSK1 depletion experiments and gene expression analysis (RT-qPCR).
  • Investigating the contribution of ERK and p38α kinases to MSK1 activation.

Main Results:

  • MSK1 is upregulated and activated upon RAF1 oncogenic stress, with increased nuclear localization at the INK4AB/ARF locus.
  • MSK1 mediates histone H3 serine 28 phosphorylation (H3S28ph) at the INK4AB/ARF locus.
  • MSK1 activation promotes rapid transcription of p15(INK4B) and p16(INK4A), overriding H3K27me3 repression.
  • MSK1 depletion reduces H3S28ph and expression of p15(INK4B) and p16(INK4A) in RAF1-expressing cells.
  • ERK and p38α kinases contribute to MSK1 activation in oncogene-induced senescence.

Conclusions:

  • MSK1 plays a critical role in the rapid transcriptional activation of tumor suppressor genes p15(INK4B) and p16(INK4A) in response to oncogenic RAF1 signaling.
  • MSK1-mediated H3S28 phosphorylation is a key mechanism for overcoming Polycomb-mediated repression and inducing cellular senescence.
  • The ERK/p38α-MSK1 pathway is essential for oncogene-induced senescence via regulation of the INK4AB/ARF locus.

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