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The Keap1 BTB/POZ Dimerization Function Is Required to Sequester Nrf2 in Cytoplasm
Open accessAbstract
Transactivation of phase II detoxification enzymes and antioxidant proteins is mediated by the Cap'N'Collar transcription factor, Nrf2, which is sequestered in the cytoplasm by the actin-binding protein Keap1. Mutation of a conserved serine (S104A) within the Keap1 BTB/POZ domain disrupts Keap1 dimerization and eliminates the ability of Keap1 to sequester Nrf2 in the cytoplasm and repress Nrf2 transactivation. Disruption of endogenous Keap1 dimerization using BTB/POZ dominant negative proteins also inhibits the ability of Keap1 to retain Nrf2 in the cytoplasm. Exposure to an electrophilic agent that induces Nrf2 release and nuclear translocation disrupts formation of a Keap1 complex in vivo. Collectively, these data support the conclusion that Keap1 dimerization is required for Nrf2 sequestration and transcriptional repression. Furthermore, exposure to inducing agents disrupts the Keap1 dimerization function and results in Nrf2 release.
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“Nrf2 association requires the homodimerization of Keap1 [74].”
From Nrf2 and Oxidative Stress: A General Overview of Mechanisms and Implications in Human Disease (2022) · cites this paper as [74]
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Metadata
- Authors
- Zipper, L. M., & Mulcahy, R. T.
- Affiliations
- University of Wisconsin–Madison (US)
- Corresponding author
- Zipper, Laurie M.
- ORCID
- Mulcahy, R. Timothy
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2002-09
- Volume
- 277
- Issue
- 39
- Pages
- 36544-36552
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2029022033
- Cited by
- 366
- References
- 57
- Citations by year
- 2026: 6 · 2025: 17 · 2024: 12 · 2023: 14 · 2022: 13 · 2021: 13 · 2020: 23 · 2019: 9 · 2018: 16 · 2017: 23 · 2016: 13 · 2015: 11 · 2014: 18 · 2013: 7 · 2012: 15
- FWCI
- 6.27
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5r01es009749-04)
- National Institute of Environmental Health Sciences (ES 09749)
- 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, BTB/POZ domain, protein dimerization, cytoplasmic sequestration, transcriptional repression, phase II enzymes, antioxidant proteins, electrophilic stress, Nrf2 nuclear translocation, dominant-negative mutant
- MeSH terms
- Kelch-Like ECH-Associated Protein 1, Amino Acid Sequence, Animals, Carrier Proteins, Cell Line, Cell Nucleus, Cytoplasm, Cytoskeletal Proteins, DNA-Binding Proteins, Humans, Luciferases, Luminescent Proteins, Microscopy, Fluorescence, Models, Biological, Molecular Sequence Data, Mutation, Precipitin Tests, Serine, Transcription, Genetic, Transfection, Blotting, Western, Transcriptional Activation, Trans-Activators, Mutagenesis, Site-Directed, Sequence Homology, Amino Acid, Protein Structure, Tertiary, Genes, Reporter, DNA, Complementary, Dimerization, Mitogen-Activated Protein Kinases, Active Transport, Cell Nucleus, p38 Mitogen-Activated Protein Kinases, Adaptor Proteins, Signal Transducing, Green Fluorescent Proteins, NF-E2-Related Factor 2, Mice
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