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Review ArticleReview Article

Molecular Basis of Electrophilic and Oxidative Defense: Promises and Perils of Nrf2

Qiang Ma and Xiaoqing He
David R. Sibley, ASSOCIATE EDITOR
Pharmacological Reviews October 2012, 64 (4) 1055-1081; DOI: https://doi.org/10.1124/pr.110.004333
Qiang Ma
Receptor Biology Laboratory, Toxicology and Molecular Biology Branch, Health Effects Laboratory Division, National Institute for Occupational Safety and Health, Centers for Disease Control and Prevention, Morgantown, West Virginia
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Xiaoqing He
Receptor Biology Laboratory, Toxicology and Molecular Biology Branch, Health Effects Laboratory Division, National Institute for Occupational Safety and Health, Centers for Disease Control and Prevention, Morgantown, West Virginia
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David R. Sibley
Receptor Biology Laboratory, Toxicology and Molecular Biology Branch, Health Effects Laboratory Division, National Institute for Occupational Safety and Health, Centers for Disease Control and Prevention, Morgantown, West Virginia
Roles: ASSOCIATE EDITOR
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Abstract

Induction of drug-metabolizing enzymes through the antioxidant response element (ARE)-dependent transcription was initially implicated in chemoprevention against cancer by antioxidants. Recent progress in understanding the biology and mechanism of induction revealed a critical role of induction in cellular defense against electrophilic and oxidative stress. Induction is mediated through a novel signaling pathway via two regulatory proteins, the nuclear factor erythroid 2-related factor 2 (Nrf2) and the Kelch-like erythroid cell-derived protein with CNC homology-associated protein 1 (Keap1). Nrf2 binds to Keap1 at a two site-binding interface and is ubiquitinated by the Keap1/cullin 3/ring box protein-1-ubiquitin ligase, resulting in a rapid turnover of Nrf2 protein. Electrophiles and oxidants modify critical cysteine thiols of Keap1 and Nrf2 to inhibit Nrf2 ubiquitination, leading to Nrf2 activation and induction. Induction increases stress resistance critical for cell survival, because knockout of Nrf2 in mice increased susceptibility to a variety of toxicity and disease processes. Collateral to diverse functions of Nrf2, genome-wide search has led to the identification of a plethora of ARE-dependent genes regulated by Nrf2 in an inducer-, tissue-, and disease-dependent manner to control drug metabolism, antioxidant defense, stress response, proteasomal degradation, and cell proliferation. The protective nature of Nrf2 could also be hijacked in a number of pathological conditions by means of somatic mutation, epigenetic alteration, and accumulation of disruptor proteins, promoting drug resistance in cancer and pathologic liver features in autophagy deficiency. The repertoire of ARE inducers has expanded enormously; the therapeutic potential of the inducers has been examined beyond cancer prevention. Developing potent and specific ARE inducers and Nrf2 inhibitors holds certain new promise for the prevention and therapy against cancer, chronic disease, and toxicity.

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  • This article is available online at http://pharmrev.aspetjournals.org.

    http://dx.doi.org/10.1124/pr.110.004333.

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In this issue

Pharmacological Reviews: 64 (4)
Pharmacological Reviews
Vol. 64, Issue 4
1 Oct 2012
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Review ArticleReview Article

NRF2 FUNCTION AND SIGNALING

Qiang Ma and Xiaoqing He
Pharmacological Reviews October 1, 2012, 64 (4) 1055-1081; DOI: https://doi.org/10.1124/pr.110.004333

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Review ArticleReview Article

NRF2 FUNCTION AND SIGNALING

Qiang Ma and Xiaoqing He
Pharmacological Reviews October 1, 2012, 64 (4) 1055-1081; DOI: https://doi.org/10.1124/pr.110.004333
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  • Article
    • Abstract
    • I. Introduction
    • II. The Nuclear Factor Erythroid 2-Related Factor 2–Antioxidant Response Element (Nrf2-ARE) Pathway: Finding the Xenobiotic-Activated Receptor
    • III. Mechanism of Nuclear Factor Erythroid 2-Related Factor 2 Regulation: Insights from Structure
    • IV. Nuclear Factor Erythroid 2-Related Factor 2 Signaling in Disease and Toxicity: Expecting the Unexpected
    • V. Genetics and Cancer Mutation: Revealing the Perilous Side of Nuclear Factor Erythroid 2-Related Factor 2 Signaling Activation
    • VI. Targeting the Nuclear Factor Erythroid 2-Related Factor 2 Signaling-Antioxidant Response Element Pathway for Drug Development: Going beyond the Promise
    • VII. Conclusion
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