Cited by 997Genomics, phytochemicals, and oxidative stressRedox biology and oxidative stressGlutathione Transferases and Polymorphisms

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Molecular basis of the Keap1–Nrf2 system

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Suzuki, Takafumi, Yamamoto, Masayuki·2015·Free Radical Biology and Medicine

DOI 10.1016/j.freeradbiomed.2015.06.006

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Abstract

Nrf2 (NF-E2-related factor 2) is a master regulator of cellular responses against environmental stresses. Nrf2 induces the expression of detoxification and antioxidant enzymes, and Keap1 (Kelch-like ECH-associated protein 1), an adaptor subunit of Cullin 3-based E3 ubiquitin ligase, regulates Nrf2 activity. Keap1 also acts as a sensor for oxidative and electrophilic stresses. Keap1 retains multiple sensor cysteine residues that detect various stress stimuli. Increasing attention has been paid to the roles that Nrf2 plays in the protection of our bodies against drug toxicity and stress-induced diseases. On the other hand, Nrf2 is found to promote both oncogenesis and cancer cell resistance against chemotherapeutic drugs. Thus, although Nrf2 acts to protect our body from deleterious stresses, cancer cells hijack the Nrf2 activity to support their malignant growth. Nrf2 has emerged as a new therapeutic target, and both inducers and inhibitors of Nrf2 are awaited. Studies challenging the molecular basis of the Keap1-Nrf2 system functions are now critically important to improve translational studies of the system. Indeed, recent studies identified cross talk between Nrf2 and other signaling pathways, which provides new insights into the mechanisms by which the Keap1-Nrf2 system serves as a potent regulator of our health and disease.

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Authors: Suzuki, T., & Yamamoto, M.
Affiliations: Tohoku University (JP)
Corresponding author: Yamamoto, Masayuki
ORCID: Suzuki, Takafumi
Yamamoto, Masayuki
Venue: Free Radical Biology and Medicine
Publisher: Elsevier BV
Published: 2015-11
Volume: 88
Issue: Pt B
Pages: 93-100
ISSN: 0891-5849 (ISSN-L)
DOI: 10.1016/j.freeradbiomed.2015.06.006
OpenAlex: W952491933
Cited by: 995
References: 84
Citations by year: 2026: 62 · 2025: 89 · 2024: 83 · 2023: 102 · 2022: 116 · 2021: 104 · 2020: 118 · 2019: 88 · 2018: 78 · 2017: 82 · 2016: 62 · 2015: 10
FWCI: 7.53
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
www.elsevier.com/open-access/userlicense/1.0/ (am, 360 d)
doi.org/10.15223/policy-017 (stm-asf)
doi.org/10.15223/policy-037 (stm-asf)
doi.org/10.15223/policy-012 (stm-asf)
doi.org/10.15223/policy-029 (stm-asf)
doi.org/10.15223/policy-004 (stm-asf)
Locations: Free Radical Biology and Medicine (acceptedVersion)
PubMed (publishedVersion)
Funders: Ministry of Education, Culture, Sports, Science and Technology
Japan Science and Technology Agency
Japan Society for the Promotion of Science (26460354, 2611010, 24249015, 25112502)
Takeda Science Foundation
Naito Foundation
Core Research for Evolutional Science and Technology
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, oxidative stress sensing, electrophilic stress, chemoresistance, carcinogenesis, Nrf2 inhibitors, Nrf2 inducers, therapeutic target
MeSH terms: Animals, Humans, Signal Transduction, Intracellular Signaling Peptides and Proteins, NF-E2-Related Factor 2

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Molecular basis of the Keap1–Nrf2 system

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