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p38 Mitogen-activated protein kinase- and HuR-dependent stabilization of p21(Cip1) mRNA mediates the G(1)/S

Vanesa Lafarga1, Ana Cuadrado, Isabel Lopez de Silanes

  • 1CNIO (Spanish National Cancer Center), Melchor Fernandez Almagro 3, 28029 Madrid, Spain.

Molecular and Cellular Biology
|June 17, 2009
PubMed

Insights

p38 MAPK signaling stabilizes p21(Cip1) mRNA, promoting G(1) cell cycle arrest after DNA damage. This pathway enhances HuR binding to p21(Cip1) mRNA, independent of p53.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Genetics

Background:

  • p38 mitogen-activated protein kinase (MAPK) is crucial for G(2)/M cell cycle arrest following DNA damage.
  • The cyclin-dependent kinase inhibitor p21(Cip1) is vital for G(1)/S cell cycle arrest induced by gamma radiation.

Purpose of the Study:

  • To investigate the role of p38 MAPK in the G(1)/S cell cycle transition.
  • To elucidate the mechanism by which p38 MAPK influences p21(Cip1) levels during DNA damage response.

Main Methods:

  • Inhibition of p38 MAPK activity.
  • Analysis of p21(Cip1) mRNA and protein levels.
  • Investigation of mRNA binding protein HuR phosphorylation and localization.
  • Assessment of HuR binding to p21(Cip1) mRNA.

Main Results:

  • Inhibition of p38 MAPK reduced p21(Cip1) accumulation and impaired G(1) cell cycle arrest.
  • p38 MAPK was found to stabilize p21(Cip1) mRNA, not affect transcription or protein stability.
  • p38 MAPK phosphorylates HuR at Thr118, leading to its cytoplasmic accumulation and enhanced binding to p21(Cip1) mRNA.

Conclusions:

  • p38 MAPK signaling is essential for p21(Cip1) mRNA stabilization and G(1)/S cell cycle arrest in response to DNA damage.
  • The p38 MAPK-HuR interaction represents a p53-independent mechanism for regulating p21(Cip1) levels at the G(1)/S checkpoint.

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