The DOI matches its Crossref record; 33 of the 33 references it cites were found in a registry or an index.
Oxidative Stress Sensor Keap1 Functions as an Adaptor for Cul3-Based E3 Ligase To Regulate Proteasomal Degradation of Nrf2
Open accessAbstract
Transcription factor Nrf2 is a major regulator of genes encoding phase 2 detoxifying enzymes and antioxidant stress proteins in response to electrophilic agents and oxidative stress. In the absence of such stimuli, Nrf2 is inactive owing to its cytoplasmic retention by Keap1 and rapid degradation through the proteasome system. We examined the contribution of Keap1 to the rapid turnover of Nrf2 (half-life of less than 20 min) and found that a direct association between Keap1 and Nrf2 is required for Nrf2 degradation. In a series of domain function analyses of Keap1, we found that both the BTB and intervening-region (IVR) domains are crucial for Nrf2 degradation, implying that these two domains act to recruit ubiquitin-proteasome factors. Indeed, Cullin 3 (Cul3), a subunit of the E3 ligase complex, was found to interact specifically with Keap1 in vivo. Keap1 associates with the N-terminal region of Cul3 through the IVR domain and promotes the ubiquitination of Nrf2 in cooperation with the Cul3-Roc1 complex. These results thus provide solid evidence that Keap1 functions as an adaptor of Cul3-based E3 ligase. To our knowledge, Nrf2 and Keap1 are the first reported mammalian substrate and adaptor, respectively, of the Cul3-based E3 ligase system.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the citing paper
“Nrf2 regulates the expression of a multitude of antioxidant and phase II enzyme genes and is negatively regulated by Kelch-like ECH-associated protein (Keap1) [49], a substrate adaptor protein that binds to Nrf2 in the cytosol to facilitate its polyubiquitination by the Cullin 3 (Cul3) E3 ubiquitin ligase for proteasomal degradation [50,51,52].”
From Nrf2 and Oxidative Stress: A General Overview of Mechanisms and Implications in Human Disease (2022) · cites this paper as [51]
In the citing paper
“The actual mechanism by which rapamycin increases Nrf2 levels is not completely elucidated; however, this seems to occur at the level of protein stabilization rather than increasing Nrf2 gene expression because rapamycin did not increase Nrf2 mRNA levels, but decreased Keap1, a protein that triggers Nrf2 degradation (Kobayashi et al., 2004).”
From Rapamycin inhibits the secretory phenotype of senescent cells by a Nrf2-independent mechanism (2017) · cites this paper as Kobayashi et al., 2004
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
Hershko, A., & Ciechanover, A. (1998) · Annual Review of Biochemistry · doi:10.1146/annurev.biochem.67.1.425 · Cited by 8,840
Dinkova-Kostova, A. T., Holtzclaw, W. D., Cole, R. N., Itoh, K., Wakabayashi, N., Katoh, Y., Yamamoto, M., & Talalay, P. (2002) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.172398899 · Cited by 1,947
Structure of the Cul1–Rbx1–Skp1–F boxSkp2 SCF ubiquitin ligase complex
Zheng, N., Schulman, B. A., Song, L., Miller, J. J., Jeffrey, P. D., Wang, P., Chu, C., Koepp, D. M., Elledge, S. J., Pagano, M., et al. (2002) · Nature · doi:10.1038/416703a · Cited by 1,507
Zhang, D. D., & Hannink, M. (2003) · Molecular and Cellular Biology · doi:10.1128/mcb.23.22.8137-8151.2003 · Cited by 1,480
HIF-1 and mechanisms of hypoxia sensing
Semenza, G. L. (2001) · Current Opinion in Cell Biology · doi:10.1016/s0955-0674(00)00194-0 · Cited by 1,301
Nrf2 Is a Direct PERK Substrate and Effector of PERK-Dependent Cell Survival
Cullinan, S. B., Zhang, D. D., Hannink, M., Arvisais, E. W., Kaufman, R. J., & Diehl, J. A. (2003) · Molecular and Cellular Biology · doi:10.1128/mcb.23.20.7198-7209.2003 · Cited by 1,233
Regulatory Mechanisms Controlling Gene Expression Mediated by the Antioxidant Response Element
Nguyen, T., Sherratt, P. J., & Pickett, C. B. (2003) · The Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev.pharmtox.43.100901.140229 · Cited by 1,232
McMahon, M., Itoh, K., Yamamoto, M., & Hayes, J. D. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m300931200 · Cited by 1,141
The structure of the G protein heterotrimer Giα1β1γ2
Wall, M. A., Coleman, D. E., Lee, E. N., Iñiguez-Lluhı́, J. A., Posner, B. A., Gilman, A. G., & Sprang, S. R. (1995) · Cell · doi:10.1016/0092-8674(95)90220-1 · Cited by 1,140
Wakabayashi, N., Dinkova-Kostova, A. T., Holtzclaw, W. D., Kang, M.-I., Kobayashi, A., Yamamoto, M., Kensler, T. W., & Talalay, P. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0307301101 · Cited by 986 · cited 5×
“The association between Cul3 and Keap1 Cys point mutants (27) was examined by immunoprecipitation (upper panel) as described above.”
BackgroundMethodInfluential
Cited by
Sorted by citations
Items 1,001–1,003 of 1,003
Dietary phytochemicals targeting Nrf2 for chemoprevention in breast cancer
Wang, P., Long, F., Lin, H., & Wang, T. (2022) · Food & Function · doi:10.1039/d2fo00186a · Cited by 28
Zhou, S., Ye, W., Duan, X., Zhang, M., & Wang, J. (2013) · Digestive Diseases and Sciences · doi:10.1007/s10620-012-2537-1 · Cited by 18
RetractedThe complex role of NRF2 in cancer: A genomic view
Praslicka, B. J., Kerins, M. J., & Ooi, A. (2016) · Current Opinion in Toxicology · doi:10.1016/j.cotox.2016.09.003 · Cited by 14
Metadata
- Authors
- Kobayashi, A., Kang, M.-I., Okawa, H., Ohtsuji, M., Zenke, Y., Chiba, T., Igarashi, K., & Yamamoto, M.
- Affiliations
- University of Tsukuba (JP)
- Hiroshima University (JP)
- Tokyo Metropolitan Institute of Medical Science (JP)
- Corresponding author
- Yamamoto, Masayuki
- Venue
- Molecular and Cellular Biology
- Publisher
- Informa UK Limited
- Published
- 2004-08-01
- Volume
- 24
- Issue
- 16
- Pages
- 7130-7139
- ISSN
- 0270-7306 (ISSN-L)
- 1098-5549
- PMC
- PMC479737
- OpenAlex
- W2155324869
- Cited by
- 2,224
- References
- 33
- Citations by year
- 2026: 100 · 2025: 102 · 2024: 116 · 2023: 137 · 2022: 154 · 2021: 123 · 2020: 182 · 2019: 121 · 2018: 122 · 2017: 122 · 2016: 140 · 2015: 132 · 2014: 95 · 2013: 100 · 2012: 84
- FWCI
- 14.20
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Molecular and Cellular Biology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics, phytochemicals, and oxidative stress
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Keywords
- Keap1, Nrf2, CUL3, E3 ubiquitin ligase, adaptor proteins, proteasomal degradation, ubiquitination, BTB domain, ROC1, oxidative stress, antioxidant response
- MeSH terms
- Kelch-Like ECH-Associated Protein 1, Animals, Cell Line, Cysteine Endopeptidases, DNA-Binding Proteins, Humans, Multienzyme Complexes, Proteins, Recombinant Fusion Proteins, Transcription Factors, Trans-Activators, Protein Structure, Tertiary, Oxidative Stress, Cell Cycle Proteins, Ubiquitin, Ubiquitin-Protein Ligases, Cullin Proteins, Macromolecular Substances, Proteasome Endopeptidase Complex, Intracellular Signaling Peptides and Proteins, Basic-Leucine Zipper Transcription Factors, NF-E2-Related Factor 2, Mice, Fanconi Anemia Complementation Group Proteins
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
