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MSK2 inhibits p53 activity in the absence of stress

Susana Llanos1, Ana Cuadrado, Manuel Serrano

  • 1Spanish National Cancer Research Centre, Madrid, Spain. sllanos@cnio.es

Science Signaling
|October 3, 2009
PubMed

Insights

Mitogen- and stress-activated kinase 2 (MSK2) inhibits the transcription factor p53. Upon apoptotic stimuli, MSK2 degrades, relieving p53 inhibition and promoting apoptosis.

Area of Science:

  • Molecular Biology
  • Cell Signaling
  • Cancer Research

Background:

  • Mitogen- and stress-activated kinase 2 (MSK2) is known to regulate cellular responses.
  • The transcription factor p53 plays a critical role in tumor suppression and apoptosis.
  • The precise mechanisms by which MSK2 influences p53 activity remain incompletely understood.

Purpose of the Study:

  • To elucidate the mechanisms by which MSK2 inhibits the transcriptional activity of p53.
  • To investigate the role of MSK2 in regulating p53 target gene expression under basal and stress conditions.
  • To determine how MSK2-mediated inhibition of p53 is regulated during apoptosis.

Main Methods:

  • Investigated MSK2's effect on p53 target gene expression.
  • Assessed the role of MSK2 kinase activity and upstream signaling in p53 inhibition.
  • Examined the interaction between MSK2, p300, and the Noxa promoter.
  • Monitored MSK2 degradation during apoptotic stimuli.

Main Results:

  • MSK2 selectively suppressed a subset of p53 target genes in the absence of stress.
  • This basal inhibition was independent of MSK2 kinase activity and upstream signaling.
  • MSK2 interacted with and inhibited the p53 coactivator p300, associating with the Noxa promoter.
  • Apoptotic stimuli led to MSK2 degradation, releasing p53 inhibition and enabling Noxa transactivation.

Conclusions:

  • MSK2 employs a novel mechanism to inhibit p53 transcriptional activity.
  • MSK2 directly interacts with p300 to modulate p53 coactivation.
  • Regulation of MSK2 stability is crucial for p53-mediated apoptosis in response to stress.

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