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National Institute of Environmental Health Sciences

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Your Environment. Your Health.

Publication Detail

Title: An internal ribosomal entry site mediates redox-sensitive translation of Nrf2.

Authors: Li, Wenge; Thakor, Nehal; Xu, Eugenia Y; Huang, Ying; Chen, Chi; Yu, Rong; Holcik, Martin; Kong, Ah-Ng

Published In Nucleic Acids Res, (2010 Jan)

Abstract: Nrf2 plays pivotal roles in coordinating the antioxidant response and maintaining redox homeostasis. Nrf2 expression is exquisitely regulated; Nrf2 expression is suppressed under unstressed conditions but strikingly induced under oxidative stress. Previous studies showed that stress-induced Nrf2 up-regulation results from both the inhibition of Nrf2 degradation and enhanced Nrf2 translation. In the present study, we elucidate the mechanism underlying translational control of Nrf2. An internal ribosomal entry site (IRES) was identified within the 5' untranslated region of human Nrf2 mRNA. The IRES(Nrf2) contains a highly conserved 18S rRNA binding site (RBS) that is required for internal initiation. This IRES(Nrf2) also contains a hairpin structured inhibitory element (IE) located upstream of the RBS. Deletion of this IE remarkably enhanced translation. Significantly, treatment of cells with hydrogen peroxide (H(2)O(2)) and phyto-oxidant sulforaphane further stimulated IRES(Nrf2)-mediated translation initiation despite the attenuation of global protein synthesis. Polyribosomal profile assay confirmed that endogenous Nrf2 mRNAs were recruited into polysomal fractions under oxidative stress conditions. Collectively, these data demonstrate that Nrf2 translation is suppressed under normal conditions and specifically enhanced upon oxidant exposure by internal initiation, and provide a mechanistic explanation for translational control of Nrf2 by oxidative stress.

PubMed ID: 19934254 Exiting the NIEHS site

MeSH Terms: 5' Untranslated Regions*; Base Sequence; Binding Sites; Cell Line; Humans; Molecular Sequence Data; NF-E2-Related Factor 2/biosynthesis; NF-E2-Related Factor 2/genetics*; Oxidants/pharmacology; Oxidation-Reduction; Oxidative Stress*; Polyribosomes/metabolism; Protein Biosynthesis*; RNA, Messenger/metabolism; RNA, Ribosomal, 18S/metabolism

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