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H2O2-dependent Hyperoxidation of Peroxiredoxin 6 (Prdx6) Plays a Role in Cellular Toxicity via Up-regulation of iPLA2 Activity*S⃞

By So Yong Kim, Hee-Yeon Jo, Mi Hye Kim, Yun-yi Cha, Sung Won Choi, Jae-Hyuck Shim, Tae Jin Kim and Ki-Young Lee

Abstract

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 μm), 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

Topics: Enzyme Catalysis and Regulation
Publisher: American Society for Biochemistry and Molecular Biology
OAI identifier: oai:pubmedcentral.nih.gov:2662274
Provided by: PubMed Central
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