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Protection against electrophile and oxidant stress by induction of the phase 2 response: Fate of cysteines of the Keap1 sensor modified by inducers
Open accessAbstract
Induction of a family of phase 2 genes encoding for proteins that protect against the damage of electrophiles and reactive oxygen intermediates is potentially a major strategy for reducing the risk of cancer and chronic degenerative diseases. Many phase 2 genes are regulated by upstream antioxidant response elements (ARE) that are targets of the leucine zipper transcription factor Nrf2. Under basal conditions, Nrf2 resides mainly in the cytoplasm bound to its cysteine-rich, Kelch domain-containing partner Keap1, which is itself anchored to the actin cytoskeleton and represses Nrf2 activity. Inducers disrupt the Keap1-Nrf2 complex by modifying two (C273 and C288) of the 25 cysteine residues of Keap1. The critical role of C273 and C288 was established by (i) their high reactivity when purified recombinant Keap1 was treated with dexamethasone mesylate and the dexamethasone-modified tryptic peptides were analyzed by mass spectrometry, and (ii) transfection of keap1 and nrf2 gene-deficient mouse embryonic fibroblasts with constructs expressing cysteine to alanine mutants of Keap1, and measurement of the ability of cotransfected Nrf2 to repress an ARE-luciferase reporter. Reaction of Keap1 with inducers results in formation of intermolecular disulfide bridges, probably between C273 of one Keap1 molecule and C288 of a second. Evidence for formation of such dimers was obtained by 2D PAGE of extracts of cells treated with inducers, and by the demonstration that whereas C273A and C288A mutants of Keap1 alone could not repress Nrf2 activation of the ARE-luciferase reporter, an equal mixture of these mutant constructs restored repressor activity.
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“Dissociation of Nrf2 from Keap1 occurs through the oxidative modification of specific stress-sensing cysteine residues of Keap1 (Figure 6) [55].”
From Nrf2 and Oxidative Stress: A General Overview of Mechanisms and Implications in Human Disease (2022) · cites this paper as [55]
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Hayes, J. D., Flanagan, J. U., & Jowsey, I. R. (2004) · The Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev.pharmtox.45.120403.095857 · Cited by 3,565
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The Nrf2-antioxidant response element signaling pathway and its activation by oxidative stress
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Metadata
- Authors
- Wakabayashi, N., Dinkova-Kostova, A. T., Holtzclaw, W. D., Kang, M.-I., Kobayashi, A., Yamamoto, M., Kensler, T. W., & Talalay, P.
- Affiliations
- Johns Hopkins University (US)
- The Lewis B. and Dorothy Cullman Cancer Chemoprotection Center, Department of Pharmacology and Molecular Sciences, School of Medicine, and Department of Environmental Health Sciences, Bloomberg School of Public Health, The Johns Hopkins University, Baltimore, MD 21205; and Center for Tsukuba Advanced Research Alliance and Japan Science and Technology Agency/Exploratory Research for Advanced Technology Environmental Response Project, University of Tsukuba, 1-1-1 Tennoudai, Tsukuba 305-8575, Japan
- Corresponding author
- Talalay, Paul
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2004-02-05
- Volume
- 101
- Issue
- 7
- Pages
- 2040-2045
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC357048
- OpenAlex
- W2125762200
- Cited by
- 986
- References
- 50
- Citations by year
- 2026: 23 · 2025: 27 · 2024: 27 · 2023: 31 · 2022: 31 · 2021: 38 · 2020: 51 · 2019: 26 · 2018: 33 · 2017: 44 · 2016: 42 · 2015: 57 · 2014: 54 · 2013: 47 · 2012: 47
- FWCI
- 22.02
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Discovery Research Portal (University of Dundee) (publishedVersion)
- Funders
- U.S. Department of Health and Human Services
- American Institute for Cancer Research
- Johns Hopkins University
- Lewis B. and Dorothy Cullman Foundation
- National Institutes of Health (1s10rr014702-01)
- National Cancer Institute (R01CA094076, CA 94076)
- National Center for Research Resources (1S10-RR14702)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics, phytochemicals, and oxidative stress
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Glutathione Transferases and Polymorphisms
- Keywords
- Keap1, Nrf2, antioxidant response element, oxidative stress, cysteine residues, dexamethasone, Kelch domain, transcriptional repression, actin cytoskeleton
- MeSH terms
- Kelch-Like ECH-Associated Protein 1, Amino Acid Sequence, Animals, Antioxidants, Carrier Proteins, Cysteine, Cytoskeletal Proteins, Disulfides, DNA-Binding Proteins, Fibroblasts, Models, Biological, Molecular Sequence Data, Oxidation-Reduction, Protein Binding, Trans-Activators, Up-Regulation, Gene Deletion, Oxidative Stress, Reducing Agents, Response Elements, Gene Silencing, Adaptor Proteins, Signal Transducing, NF-E2-Related Factor 2, Mice
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