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Molecular Pharmacology Fast Forward
First published on July 25, 2007; DOI: 10.1124/mol.107.035360

0026-895X/07/7204-1074-1081$20.00
Mol Pharmacol 72:1074-1081, 2007

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

Sally E. Purdom-Dickinson1, Elena V. Sheveleva, Haipeng Sun2, and Qin M. Chen

Interdisciplinary Graduate Program in Genetics and Genomics (S.E.P.-D.), Department of Pharmacology (E.V.S., H.S., Q.M.C.), University of Arizona, Tucson, Arizona

Nf-E2 related factor-2 (Nrf2) is a basic leucine zipper 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 reverse transcription-polymerase chain reaction failed to show an increase of Nrf2 mRNA level by H2O2 treatment. Measurements of Nrf2 protein stability excluded the possibility of Nrf2 protein stabilization. Although 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 phosphoinositide 3-kinase were able to abolish the induction of Nrf2 protein by H2O2. Although H2O2 increased phosphorylation of p70 S6 kinase, rapamycin failed to inhibit H2O2 from elevating Nrf2 protein. H2O2 also induced phosphorylation of eukaryotic translation initiation factor (eIF) 4E and eIF2{alpha} within 30 and 10 min, respectively. Inhibiting eIF4E with small interfering 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.

Received February 20, 2007; accepted July 23, 2007

Address correspondence to: Dr. Qin M. Chen, Department of Pharmacology, University of Arizona College of Medicine, 1501 N. Campbell Ave., Tucson, AZ 85724. E-mail: qchen{at}email.arizona.edu




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