Cited by 3,634Genomics, phytochemicals, and oxidative stressRedox biology and oxidative stressGlutathione Transferases and Polymorphisms

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Keap1 represses nuclear activation of antioxidant responsive elements by Nrf2 through binding to the amino-terminal Neh2 domain

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Itoh, Ken, Wakabayashi, Nobunao, Katoh, Yasutake, Ishii, Tetsuro, Igarashi, Kazuhiko, Engel, James Douglas, Yamamoto, Masayuki·1999·Genes & Development

DOI 10.1101/gad.13.1.76PMC PMC316370

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Abstract

Transcription factor Nrf2 is essential for the antioxidant responsive element (ARE)-mediated induction of phase II detoxifying and oxidative stress enzyme genes. Detailed analysis of differential Nrf2 activity displayed in transfected cell lines ultimately led to the identification of a new protein, which we named Keap1, that suppresses Nrf2 transcriptional activity by specific binding to its evolutionarily conserved amino-terminal regulatory domain. The closest homolog of Keap1 is a Drosophila actin-binding protein called Kelch, implying that Keap1 might be a Nrf2 cytoplasmic effector. We then showed that electrophilic agents antagonize Keap1 inhibition of Nrf2 activity in vivo, allowing Nrf2 to traverse from the cytoplasm to the nucleus and potentiate the ARE response. We postulate that Keap1 and Nrf2 constitute a crucial cellular sensor for oxidative stress, and together mediate a key step in the signaling pathway that leads to transcriptional activation by this novel Nrf2 nuclear shuttling mechanism. The activation of Nrf2 leads in turn to the induction of phase II enzyme and antioxidative stress genes in response to electrophiles and reactive oxygen species.

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Authors: Itoh, K., Wakabayashi, N., Katoh, Y., Ishii, T., Igarashi, K., Engel, J. D., & Yamamoto, M.
Affiliations: University of Tsukuba (JP)
Northwestern University (US)
ORCID: Itoh, Ken
Wakabayashi, Nobunao
Igarashi, Kazuhiko
Engel, James Douglas
Yamamoto, Masayuki
Venue: Genes & Development
Publisher: Cold Spring Harbor Laboratory
Published: 1999-01-01
Volume: 13
Issue: 1
Pages: 76-86
ISSN: 0890-9369 (ISSN-L)
1549-5477
DOI: 10.1101/gad.13.1.76
PMC: PMC316370
OpenAlex: W2115338196
Cited by: 3,634
References: 46
Citations by year: 2026: 141 · 2025: 162 · 2024: 177 · 2023: 196 · 2022: 222 · 2021: 184 · 2020: 217 · 2019: 196 · 2018: 187 · 2017: 197 · 2016: 177 · 2015: 177 · 2014: 167 · 2013: 162 · 2012: 142
Type: posted content
Language: en
Open access: bronze
doi.org
Locations: Genes & Development (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Funders: National Cancer Institute (R01CA080088, CA 80088)
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 sensing, phase II enzymes, reactive oxygen species, transcriptional repression, oxidative stress response
MeSH terms: Amino Acid Sequence, Animals, Antioxidants, Birds, Carrier Proteins, Cell Line, DNA-Binding Proteins, Fungal Proteins, Gene Expression Regulation, Luminescent Proteins, Molecular Sequence Data, Protein Binding, Recombinant Fusion Proteins, Transcription Factors, Transfection, Transcriptional Activation, Trans-Activators, Conserved Sequence, Sequence Homology, Amino Acid, Genes, Reporter, Oxidative Stress, Saccharomyces cerevisiae Proteins, Green Fluorescent Proteins, NF-E2-Related Factor 2

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Keap1 represses nuclear activation of antioxidant responsive elements by Nrf2 through binding to the amino-terminal Neh2 domain

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