H2O2-dependent hyperoxidation of peroxiredoxin 6 (Prdx6) plays a role in cellular toxicity via up-regulation of iPLA2 activity

J Biol Chem. 2008 Nov 28;283(48):33563-8. doi: 10.1074/jbc.M806578200. Epub 2008 Sep 30.


Peroxiredoxin 6 (Prdx6) is a bifunctional enzyme with peroxidase activity and Ca2+-independent phospholipase A2 (iPLA2) activity. Here, we report that H2O2-induced cellular toxicity acts through Prdx6 hyperoxidation. Under high concentrations of H2O2 (> 100 microm), Prdx6, and 2-Cys Prdxs were hyperoxidized. Contrary to hyperoxidation of 2-Cys Prdxs, hyperoxidation of Prdx6 was irreversible in vivo. Surprisingly, H2O2-induced cell cycle arrest at the G2/M transition correlated with hyperoxidation and increased iPLA2 activity of Prdx6. This arrest was also associated with up-regulation of p53 and p21 and with down-regulation of cyclin B1. Furthermore, the H2O2-mediated increase in iPLA2 activity was dramatically abolished in a hyperoxidation mutant (C47A), an iPLA2 mutant (S32A), and a double mutant (C47A/S32A) of Prdx6, demonstrating the essential requirement of Prdx6 C47 hyperoxidation for its iPLA2 activity. Together, our results demonstrate that H2O2-mediated hyperoxidation of Prdx6 induces cell cycle arrest at the G2/M transition through up-regulation of iPLA2 activity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Substitution
  • Cell Division / drug effects*
  • Cell Division / genetics
  • Cyclin B / biosynthesis
  • Cyclin B / genetics
  • Cyclin B1
  • Dose-Response Relationship, Drug
  • Down-Regulation / drug effects
  • Down-Regulation / genetics
  • G2 Phase / drug effects*
  • G2 Phase / genetics
  • Gene Expression Regulation, Enzymologic / drug effects*
  • Gene Expression Regulation, Enzymologic / genetics
  • Group VI Phospholipases A2 / biosynthesis*
  • Group VI Phospholipases A2 / genetics
  • HeLa Cells
  • Humans
  • Hydrogen Peroxide / pharmacology*
  • Mutation, Missense
  • Oxidants / pharmacology*
  • Oxidation-Reduction / drug effects
  • Peroxiredoxin VI / genetics
  • Peroxiredoxin VI / metabolism*
  • Tumor Suppressor Protein p53 / biosynthesis
  • Tumor Suppressor Protein p53 / genetics
  • Up-Regulation / drug effects


  • CCNB1 protein, human
  • Cyclin B
  • Cyclin B1
  • Oxidants
  • TP53 protein, human
  • Tumor Suppressor Protein p53
  • Hydrogen Peroxide
  • PRDX6 protein, human
  • Peroxiredoxin VI
  • Group VI Phospholipases A2
  • PLA2G6 protein, human