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Osmotic shock induces G1 arrest through p53 phosphorylation at Ser33 by activated p38MAPK without phosphorylation at

H Kishi1, K Nakagawa, M Matsumoto

  • 1Institute of Molecular Embryology and Genetics, Kumamoto University, Kuhonji 4-24-1, Kumamoto 862-0976, Japan.

The Journal of Biological Chemistry
|August 10, 2001
PubMed

Insights

Osmotic shock stabilizes p53 via p38(MAPK) phosphorylation at Ser(33), leading to G(1) arrest. This specific phosphorylation is crucial for p53 activation and subsequent cell cycle arrest.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Biochemistry

Background:

  • Osmotic shock can induce cellular stress responses.
  • The p53 protein is a critical tumor suppressor involved in cell cycle control.
  • Mdm2 is a negative regulator of p53.

Purpose of the Study:

  • To investigate the role of p38(MAPK) in p53 activation following osmotic shock.
  • To identify specific phosphorylation sites on p53 critical for its activation by p38(MAPK).
  • To elucidate the downstream effects of p53 activation on cell cycle progression.

Main Methods:

  • Induction of osmotic shock in cells.
  • Analysis of p53 stabilization, phosphorylation, and acetylation.
  • Use of p38(MAPK) inhibitors (SB203580) and dominant-negative MKK6.
  • Cell cycle analysis to assess G(1) arrest via p21(WAF1) induction.

Main Results:

  • Osmotic shock transiently stabilized p53, potentially via Mdm2 degradation.
  • p38(MAPK) activation led to p53 stabilization and G(1) arrest through p21(WAF1) induction.
  • Only Ser(33) of p53 was phosphorylated by p38(MAPK), which was essential for p53 activation, p300 interaction, Lys(382) acetylation, and p21(WAF1) induction.
  • Inhibition of p38(MAPK) or MKK6 blocked Ser(33) phosphorylation, Lys(382) acetylation, and p21(WAF1) induction, preventing cell cycle arrest despite p53 stabilization.

Conclusions:

  • Phosphorylation of p53 at Ser(33) by p38(MAPK) is a critical step for p53 activation following osmotic shock.
  • This specific phosphorylation event is required for downstream acetylation and induction of cell cycle arrest.
  • Ser(15) and Ser(20) phosphorylation are not essential for p53 activation in this context.

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