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Oligomeric peroxiredoxin-I is an essential intermediate for p53 to activate MST1 kinase and apoptosis

A Morinaka1, Y Funato, K Uesugi

  • 1Laboratory of Intracellular Signaling, Institute for Protein Research, Osaka University, Osaka, Japan.

Oncogene
|April 26, 2011
PubMed

Insights

Peroxiredoxin-I (PRX-I) activates Ste20-like kinase-1 (MST1) during oxidative stress, mediating p53-dependent cell death induced by anticancer drugs like cisplatin.

Area of Science:

  • Cell Biology
  • Biochemistry
  • Molecular Oncology

Background:

  • Mammalian Ste20-like kinase-1 (MST1) mediates p53-dependent cell death induced by hydrogen peroxide (H₂O₂) and anticancer drugs.
  • The precise mechanism of MST1 activation by H₂O₂ is not fully understood.

Purpose of the Study:

  • To elucidate the role of peroxiredoxin-I (PRX-I) in H₂O₂-induced MST1 activation and subsequent cell death.
  • To investigate the involvement of p53 in the PRX-I-mediated pathway.

Main Methods:

  • Cell stimulation with H₂O₂ and cisplatin.
  • RNA interference (RNAi) knockdown of PRX-I.
  • Live-cell imaging.
  • Analysis of p53-knockout mouse embryonic fibroblasts.
  • In vitro reconstitution assays with purified PRX-I and MST1.

Main Results:

  • H₂O₂ stimulation caused PRX-I oxidation, homo-oligomerization, and interaction with MST1, leading to MST1 autophosphorylation and increased kinase activity.
  • Endogenous PRX-I is essential for H₂O₂-induced MST1 activation.
  • Cisplatin treatment generated H₂O₂, induced PRX-I oligomerization, MST1 activation, and cell death in a p53-dependent manner.
  • PRX-I oligomerization and cell death induced by p53 were inhibited by the antioxidant N-acetylcysteine (NAC).
  • Purified PRX-I and MST1 proteins reconstituted H₂O₂-induced MST1 activation in vitro.

Conclusions:

  • PRX-I acts as a crucial intermediate in H₂O₂-induced MST1 activation.
  • PRX-I-mediated MST1 activation is a key pathway for p53-dependent cell death triggered by oxidative stress and anticancer agents.

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