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First published on July 25, 2007; DOI: 10.1124/mol.107.035360

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Received for publication February 23, 2007.
Revised July 20, 2007.
Accepted for publication July 23, 2007.

Translational Control of Nrf2 Protein in Activation of Antioxidant Response by Oxidants

Sally Purdom-Dickinson 1, Elena Sheveleva 1, Haipeng Sun 1, Qin M Chen 1*

1 University of Arizona

* Address correspondence to: E-mail: qchen{at}email.arizona.edu

Abstract

Nf-E2 related factor-2 (Nrf2) is a bZIP transcription factor that binds and activates the Antioxidant Response Element (ARE) in the promoters of many antioxidant and detoxification genes. We found that H2O2 treatment caused a rapid increase in endogenous Nrf2 protein level in rat cardiomyocytes. Semiquantitative or real-time RT-PCR failed to show an increase of Nrf2 mRNA level by H2O2 treatment. Measurements of Nrf2 protein stability excluded the possibility of Nrf2 protein stabilization. While inhibiting protein synthesis with cycloheximide prevented H2O2 from elevating Nrf2 protein level, RNA synthesis inhibition with actinomycin D failed to do so. Measurements of new protein synthesis with 35S-Methionine incorporation confirmed that H2O2 increased the translation of Nrf2 protein. Inhibitors of phosphinositide 3-kinase (PI3K) were able to abolish the induction of Nrf2 protein by H2O2. While H2O2 increased phosphorylation of p70 S6 kinase, rapamycin failed to inhibit H2O2 from elevating Nrf2 protein. H2O2 also induced phosphorylation of eIF4E and eIF2{alpha} within 30 and 10 mins respectively. Inhibiting eIF4E with siRNA or increasing eIF2{alpha} phosphorylation with salubrinal did not affect Nrf2 elevation by H2O2. Our data present a novel phenomenon of quick onset of the antioxidant/detoxification response via increased translation of Nrf2 by oxidants. The mechanism underlying such stress induced de novo protein translation may involve multiple components of translational machinery.


Key words: Protein Kinases (other), Phosphorylation/Dephosphorylation, Phase II enzymes, Regulation - transcriptional, Oxidative stress/antioxidants, Toxicant-induced gene express


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