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Distinct Cysteine Residues in Keap1 Are Required for Keap1-Dependent Ubiquitination of Nrf2 and for Stabilization of Nrf2 by Chemopreventive Agents and Oxidative Stress
Open accessAbstract
A common feature of diverse chemopreventive agents is the ability to activate expression of a genetic program that protects cells from reactive chemical species that, if left unchecked, would cause mutagenic DNA damage. The bZIP transcription factor Nrf2 has emerged as a key regulator of this cancer-preventive genetic program. Nrf2 is normally sequestered in the cytoplasm by a protein known as Keap1. Chemopreventive agents allow Nrf2 to escape from Keap1-mediated repression, although the molecular mechanism(s) responsible for activation of Nrf2 is not understood. In this report, we demonstrate that Keap1 does not passively sequester Nrf2 in the cytoplasm but actively targets Nrf2 for ubiquitination and degradation by the proteosome under basal culture conditions. We have identified two critical cysteine residues in Keap1, C273 and C288, that are required for Keap1-dependent ubiquitination of Nrf2. Both sulforaphane, a chemopreventive isothiocyanate, and oxidative stress enable Nrf2 to escape Keap1-dependent degradation, leading to stabilization of Nrf2, increased nuclear localization of Nrf2, and activation of Nrf2-dependent cancer-protective genes. We have identified a third cysteine residue in Keap1, C151, that is uniquely required for inhibition of Keap1-dependent degradation of Nrf2 by sulforaphane and oxidative stress. This cysteine residue is also required for a novel posttranslational modification to Keap1 that is induced by oxidative stress. We propose that Keap1 is a component of a novel E3 ubiquitin ligase complex that is specifically targeted for inhibition by both chemopreventive agents and oxidative stress.
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“Cys273 and Cys288 are required for sensing oxidative stress under both basal and stress conditions, whereas Cys151 may be required only during oxidative stress conditions [53,54].”
From Nrf2 and Oxidative Stress: A General Overview of Mechanisms and Implications in Human Disease (2022) · cites this paper as [53]
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Metadata
- Authors
- Zhang, D. D., & Hannink, M.
- Affiliations
- University of Missouri (US)
- Venue
- Molecular and Cellular Biology
- Publisher
- Informa UK Limited
- Published
- 2003-11-01
- Volume
- 23
- Issue
- 22
- Pages
- 8137-8151
- ISSN
- 0270-7306 (ISSN-L)
- 1098-5549
- PMC
- PMC262403
- OpenAlex
- W2130029858
- Cited by
- 1,480
- References
- 43
- Citations by year
- 2026: 65 · 2025: 69 · 2024: 68 · 2023: 73 · 2022: 83 · 2021: 87 · 2020: 101 · 2019: 70 · 2018: 79 · 2017: 77 · 2016: 93 · 2015: 72 · 2014: 64 · 2013: 63 · 2012: 62
- FWCI
- 11.15
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Molecular and Cellular Biology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- University of Missouri
- National Institutes of Health
- University of California, San Francisco
- National Institute of General Medical Sciences (GM 59213, R01GM059213)
- National Institute of Environmental Health Sciences (ES 11721, R21ES011721)
- 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, cysteine residues, ubiquitination, protein degradation, proteasome, chemoprevention, sulforaphane, oxidative stress, E3 ubiquitin ligase, protein stabilization, nuclear localization, post-translational modification
- MeSH terms
- Kelch-Like ECH-Associated Protein 1, Animals, Carrier Proteins, Cell Line, Cysteine, Cytoskeletal Proteins, DNA-Binding Proteins, Recombinant Proteins, Sulfoxides, Thiocyanates, Transcription, Genetic, Trans-Activators, Mutagenesis, Anticarcinogenic Agents, Sequence Deletion, Protein Structure, Tertiary, Isothiocyanates, Oxidative Stress, COS Cells, Ubiquitin, NIH 3T3 Cells, Adaptor Proteins, Signal Transducing, NF-E2-Related Factor 2, Mice
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