Cited by 1,141Genomics, phytochemicals, and oxidative stressRedox biology and oxidative stressUbiquitin and proteasome pathways

The DOI matches its Crossref record; 54 of the 54 references it cites were found in a registry or an index.

Keap1-dependent Proteasomal Degradation of Transcription Factor Nrf2 Contributes to the Negative Regulation of Antioxidant Response Element-driven Gene Expression

Open access

McMahon, Michael, Itoh, Ken, Yamamoto, Masayuki, Hayes, John D.·2003·Journal of Biological Chemistry

DOI 10.1074/jbc.m300931200

Open this paper in CoChat — free account

Abstract

Keap1 is a negative regulator of Nrf2, a bZIP transcription factor that mediates adaptation to oxidative stress. Previous studies suggested this negative regulation is a consequence of Keap1 controlling the subcellular distribution of Nrf2. We now report that Keap1 also controls the total cellular level of Nrf2 protein. In the RL34 non-transformed rat liver cell line, Nrf2 was found to accumulate rapidly in response to oxidative stress caused by treatment with sulforaphane, and the accumulation resulted from inhibition of proteasomal-mediated degradation of the bZIP protein. By heterologously expressing in COS1 cells epitope-tagged Nrf2 and an Nrf2DeltaETGE mutant lacking the Keap1-binding site, in both the presence and absence of Keap1 we demonstrate that Nrf2 is subject to ubiquitination and proteasomal degradation independently of both Keap1 and the redox environment of the cell. In oxidatively stressed cells, this is the sole mechanism responsible for Nrf2 degradation. However, under homeostatic conditions Nrf2 is subject to a substantially more rapid mode of proteasomal degradation than it is in oxidatively stressed cells, and this rapid turnover of Nrf2 requires it to interact with Keap1. Within Nrf2, the N-terminal Neh2 domain is identified as the redox-sensitive degron. These data suggest that Keap1 negatively regulates Nrf2 by both enhancing its rate of proteasomal degradation and altering its subcellular distribution.

Integrity signals

Registry

Crossref · 10.1074/jbc.m300931200

Cites

54 of 54 references verified0 citation errors · 0 not checkable

Statistics

Recomputing p-values needs the paper’s full text.

Claims the paper makes

We couldn’t retrieve this paper’s full text, so its claims and self-check weren’t run. The registry and citation checks still apply.

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?

THE UBIQUITIN SYSTEM
Hershko, A., & Ciechanover, A. (1998) · Annual Review of Biochemistry · doi:10.1146/annurev.biochem.67.1.425 · Cited by 8,840
Redox environment of the cell as viewed through the redox state of the glutathione disulfide/glutathione couple
Schafer, F. Q., & Buettner, G. R. (2001) · Free Radical Biology and Medicine · doi:10.1016/s0891-5849(01)00480-4 · Cited by 4,587
The Ubiquitin-Proteasome Proteolytic Pathway: Destruction for the Sake of Construction
Glickman, M. H., & Ciechanover, A. J. (2002) · Physiological Reviews · doi:10.1152/physrev.00027.2001 · Cited by 4,296
An Nrf2/Small Maf Heterodimer Mediates the Induction of Phase II Detoxifying Enzyme Genes through Antioxidant Response Elements
Itoh, K., Chiba, T., Takahashi, S., Ishii, T., Igarashi, K., Katoh, Y., Oyake, T., Hayashi, N., Satoh, K., Hatayama, I., et al. (1997) · Biochemical and Biophysical Research Communications · doi:10.1006/bbrc.1997.6943 · Cited by 3,999
Keap1 represses nuclear activation of antioxidant responsive elements by Nrf2 through binding to the amino-terminal Neh2 domain
Itoh, K., Wakabayashi, N., Katoh, Y., Ishii, T., Igarashi, K., Engel, J. D., & Yamamoto, M. (1999) · Genes & Development · doi:10.1101/gad.13.1.76 · Cited by 3,634
Self-citation
Direct evidence that sulfhydryl groups of Keap1 are the sensors regulating induction of phase 2 enzymes that protect against carcinogens and oxidants
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
Glutathione and glutathione-dependent enzymes represent a co-ordinately regulated defence against oxidative stress
Hayes, J. D., & McLellan, L. I. (1999) · Free Radical Research · doi:10.1080/10715769900300851 · Cited by 1,528
The Proteasome: Paradigm of a Self-Compartmentalizing Protease
Baumeister, W. P., Walz, J., Zühl, F., & Seemüller, E. (1998) · Cell · doi:10.1016/s0092-8674(00)80929-0 · Cited by 1,497
Transcription Factor Nrf2 Coordinately Regulates a Group of Oxidative Stress-inducible Genes in Macrophages
Ishii, T., Itoh, K., Takahashi, S., Sato, H., Yanagawa, T., Katoh, Y., Bannai, S., & Yamamoto, M. P. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.275.21.16023 · Cited by 1,473
The ubiquitin–proteasome pathway: on protein death and cell life
Ciechanover, A. J. (1998) · The EMBO Journal · doi:10.1093/emboj/17.24.7151 · Cited by 1,419
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
Untitled work
(2002) · PubMed · Cited by 1,190
REGULATION OF GENE EXPRESSION BY REACTIVE OXYGEN
Dalton, T. P., Shertzer, H. G., & Puga, A. (1999) · The Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev.pharmtox.39.1.67 · Cited by 1,123
Phosphorylation of Nrf2 at Ser-40 by Protein Kinase C Regulates Antioxidant Response Element-mediated Transcription*
Huang, H.-C., Nguyen, T., & Pickett, C. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m206911200 · Cited by 1,070
Ubiquitin-dependent c-Jun degradation in vivo is mediated by the δ domain
Treier, M., Staszewski, L. M., & Bohmann, D. (1994) · Cell · doi:10.1016/s0092-8674(94)90502-9 · Cited by 919
The N-end rule: functions, mysteries, uses
Varshavsky, A. (1996) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.93.22.12142 · Cited by 859
The Cap'n'Collar basic leucine zipper transcription factor Nrf2 (NF-E2 p45-related factor 2) controls both constitutive and inducible expression of intestinal detoxification and glutathione biosynthetic enzymes.
McMahon, M. J., Itoh, K., Yamamoto, M. P., Chanas, S. A., Henderson, C. J., McLellan, L. I., Wolf, C. R., Cavin, C., & Hayes, J. D. (2001) · PubMed · Cited by 657
NRF2, a member of the NFE2 family of transcription factors, is not essential for murine erythropoiesis, growth, and development
Chan, K., Lu, R., Chang, J. C., & Kan, Y. W. (1996) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.93.24.13943 · Cited by 643
Increased Protein Stability as a Mechanism That Enhances Nrf2-mediated Transcriptional Activation of the Antioxidant Response Element
Nguyen, T., Sherratt, P. J., Huang, H.-C., Yang, C. S., & Pickett, C. B. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m207293200 · Cited by 615
The kelch repeat superfamily of proteins: propellers of cell function
Adams, J. C., Kelso, R., & Cooley, L. (2000) · Trends in Cell Biology · doi:10.1016/s0962-8924(99)01673-6 · Cited by 603
Enhanced Expression of the Transcription Factor Nrf2 by Cancer Chemopreventive Agents: Role of Antioxidant Response Element-Like Sequences in the nrf2 Promoter
Kwak, M.-K., Itoh, K., Yamamoto, M. P., & Kensler, T. W. (2002) · Molecular and Cellular Biology · doi:10.1128/mcb.22.9.2883-2892.2002 · Cited by 597
Electrophile Response Element-mediated Induction of the Cystine/Glutamate Exchange Transporter Gene Expression
Sasaki, H., Sato, H., Kuriyama-Matsumura, K., Sato, K., Maebara, K., Wang, H., Tamba, M., Itoh, K., Yamamoto, M. P., & Bannai, S. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m208704200 · Cited by 544
Two domains of Nrf2 cooperatively bind CBP, a CREB binding protein, and synergistically activate transcription
Katoh, Y., Itoh, K., Yoshida, E., Miyagishi, M., Fukamizu, A., & Yamamoto, M. P. (2001) · Genes to Cells · doi:10.1046/j.1365-2443.2001.00469.x · Cited by 533
Transcriptional regulation of the rat NAD(P)H:quinone reductase gene
Favreau, L. V., & Pickett, C. B. (1991) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(20)64358-7 · Cited by 497
Degradation of transcription factor Nrf2 via the ubiquitin-proteasome pathway and stabilization by cadmium
Stewart, D., Killeen, E., Naquin, R., Alam, S., & Alam, J. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m209195200 · Cited by 463
Dietary indoles and isothiocyanates that are generated from cruciferous vegetables can both stimulate apoptosis and confer protection against DNA damage in human colon cell lines.
Bonnesen, C., Eggleston, I. M., & Hayes, J. D. (2001) · PubMed · Cited by 463
Loss of the Nrf2 transcription factor causes a marked reduction in constitutive and inducible expression of the glutathione S-transferase Gsta1, Gsta2, Gstm1, Gstm2, Gstm3 and Gstm4 genes in the livers of male and female mice
CHANAS, S. A., JIANG, Q., McMAHON, M., McWALTER, G. K., McLELLAN, L. I., ELCOMBE, C. R., HENDERSON, C. J., WOLF, C. R., MOFFAT, G. J., ITOH, K., et al. (2002) · Biochemical Journal · doi:10.1042/bj20020320 · Cited by 460
Ubiquitin in chains
Pickart, C. M. (2000) · Trends in Biochemical Sciences · doi:10.1016/s0968-0004(00)01681-9 · Cited by 458
Integration and diversity of the regulatory network composed of Maf and CNC families of transcription factors
Motohashi, H., O'Connor, T., Katsuoka, F., Engel, J. D., & Yamamoto, M. P. (2002) · Gene · doi:10.1016/s0378-1119(02)00788-6 · Cited by 456
Chemical and molecular regulation of enzymes that detoxify carcinogens.
Prestera, T., Holtzclaw, W. D., Zhang, Y., & Talalay, P. (1993) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.90.7.2965 · Cited by 416
Transcriptional Regulation of the Antioxidant Response Element
Nguyen, T., Huang, H.-C., & Pickett, C. B. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.m000361200 · Cited by 375
The Keap1 BTB/POZ dimerization function is required to sequester Nrf2 in cytoplasm
Zipper, L. M., & Mulcahy, R. T. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m206530200 · Cited by 366
Glutathione redox potential in response to differentiation and enzyme inducers
Kirlin, W. G., Cai, J., Thompson, S. A., Dı́az, D., Kavanagh, T. J., & Jones, D. P. (1999) · Free Radical Biology and Medicine · doi:10.1016/s0891-5849(99)00145-8 · Cited by 359
Role of Transcription Factor Nrf2 in the Induction of Hepatic Phase 2 and Antioxidative Enzymes in vivo by the Cancer Chemoprotective Agent, 3H-1, 2-Dithiole-3-thione
Kwak, M., Itoh, K., Yamamoto, M. P., Sutter, T. R., & Kensler, T. W. (2001) · Molecular Medicine · doi:10.1007/bf03401947 · Cited by 357
Identification of the interactive interface and phylogenic conservation of the Nrf2‐Keap1 system
Kobayashi, M., Itoh, K., Suzuki, T., Osanai, H., Nishikawa, K., Katoh, Y., Takagi, Y., & Yamamoto, M. P. (2002) · Genes to Cells · doi:10.1046/j.1365-2443.2002.00561.x · Cited by 340
Role of transcription factor Nrf2 in the induction of hepatic phase 2 and antioxidative enzymes in vivo by the cancer chemoprotective agent, 3H-1, 2-dimethiole-3-thione.
Kwak, M.-K., Itoh, K., Yamamoto, M. P., Sutter, T. R., & Kensler, T. W. (2001) · PubMed Central · Cited by 330
Oxidative Stress and Antioxidant Defenses in Biology
Ahmad, S. (1995) · Springer eBooks · doi:10.1007/978-1-4615-9689-9 · Cited by 322
Hemin-induced Activation of the Thioredoxin Gene by Nrf2
Kim, Y. C., Masutani, H., Yamaguchi, Y., Itoh, K., Yamamoto, M. P., & Yodoi, J. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m100103200 · Cited by 313
Subcellular localization of proteasomes and their regulatory complexes in mammalian cells
BROOKS, P., Fuertes, G., Murray, R. Z., Bose, S., Knecht, E., Rechsteiner, M., Hendil, K. B., Tanaka, K., Dyson, J., & Rivett, A. J. (2000) · Biochemical Journal · doi:10.1042/bj3460155 · Cited by 304
Functional characterization and role of INrf2 in antioxidant response element-mediated expression and antioxidant induction of NAD(P)H:quinone oxidoreductase1 gene
Dhakshinamoorthy, S., & Jaiswal, A. K. (2001) · Oncogene · doi:10.1038/sj.onc.1204506 · Cited by 290
A Sulforaphane Analogue That Potently Activates the Nrf2-dependent Detoxification Pathway
Morimitsu, Y., Nakagawa, Y., Hayashi, K., Fujii, H., Kumagai, T., Nakamura, Y., Osawa, T., Horio, F., Itoh, K., Iida, K., et al. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m110244200 · Cited by 274
Functional overlap of sequences that activate transcription and signal ubiquitin-mediated proteolysis
Salghetti, S. E., Muratani, M., Wijnen, H., Futcher, B., & Tansey, W. P. (2000) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.97.7.3118 · Cited by 265
Up-Regulation of the Human γ-Glutamylcysteine Synthetase Regulatory Subunit Gene Involves Binding of Nrf-2 to an Electrophile Responsive Element
Moinova, H., & Mulcahy, R. (1999) · Biochemical and Biophysical Research Communications · doi:10.1006/bbrc.1999.1109 · Cited by 245
The Heme-Responsive Element of the Mouse Heme Oxygenase-1 Gene Is an Extended AP-1 Binding Site That Resembles the Recognition Sequences for MAF and NF-E2 Transcription Factors
Inamdar, N. M., Ahn, Y. I., & Alam, J. (1996) · Biochemical and Biophysical Research Communications · doi:10.1006/bbrc.1996.0637 · Cited by 195
Microarray Analysis Reveals an Antioxidant Responsive Element-driven Gene Set Involved in Conferring Protection from an Oxidative Stress-induced Apoptosis in IMR-32 Cells
Li, J., Lee, J., & Johnson, J. A. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m109380200 · Cited by 193
Chemoprevention of aflatoxin B1 hepatocarcinogenesis by coumarin, a natural benzopyrone that is a potent inducer of aflatoxin B1-aldehyde reductase, the glutathione S-transferase A5 and P1 subunits, and NAD(P)H:quinone oxidoreductase in rat liver.
Kelly, V. P., Ellis, E. M., Manson, M. M., Chanas, S. A., Moffat, G. J., McLeod, R., Judah, D. J., Neal, G. E., & Hayes, J. D. (2000) · PubMed · Cited by 147
Clastosome: A Subtype of Nuclear Body Enriched in 19S and 20S Proteasomes, Ubiquitin, and Protein Substrates of Proteasome
Lafarga, M., Berciano, M. T., Pena, E., Mayo, I., Castaño, J. G., Bohmann, D., Rodrigues, J. P., Tavanez, J. P., & Carmo‐Fonseca, M. (2002) · Molecular Biology of the Cell · doi:10.1091/mbc.e02-03-0122 · Cited by 140
Nrf2 degradation by the ubiquitin proteasome pathway is inhibited by KIAA0132, the human homolog to INrf2
Sekhar, K. R., Yan, X. X., & Freeman, M. L. (2002) · Oncogene · doi:10.1038/sj.onc.1205905 · Cited by 139
Nuclear‐specific degradation of Far1 is controlled by the localization of the F‐box protein Cdc4
Blondel, M., Galan, J., Chi, Y., Lafourcade, C., Longaretti, C., Deshaies, R. J., & Peter, M. (2000) · The EMBO Journal · doi:10.1093/emboj/19.22.6085 · Cited by 110
The biochemistry of preneoplastic liver: a common metabolic pattern in hepatocyte nodules
Farber, E. (1984) · Canadian Journal of Biochemistry and Cell Biology · doi:10.1139/o84-066 · Cited by 101
Ubiquitin-mediated Proteolysis of a Short-lived Regulatory Protein Depends on Its Cellular Localization
Lenk, U., & Sommer, T. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.m006949200 · Cited by 51
Inhibition of the 26S Proteasome Induces Expression of GLCLC, the Catalytic Subunit for γ-Glutamylcysteine Synthetase
Sekhar, K. R., Soltaninassab, S. R., Borrelli, M. J., Xu, Z., Meredith, M. J., Domann, F. E., & Freeman, M. L. (2000) · Biochemical and Biophysical Research Communications · doi:10.1006/bbrc.2000.2419 · Cited by 49
Cic1, an adaptor protein specifically linking the 26S proteasome to its substrate, the SCF component Cdc4
Jäger, S., Strayle, J., Heinemeyer, W., & Wolf, D. H. (2001) · The EMBO Journal · doi:10.1093/emboj/20.16.4423 · Cited by 45
In mouse myoblasts nuclear prosomes are associated with the nuclear matrix and accumulate preferentially in the perinucleolar areas
Conto, F. D., Pilotti, E., Razin, S. V., Ferraglia, F., Géraud, G., Arcangeletti, C., & Scherrer, K. (2000) · Journal of Cell Science · doi:10.1242/jcs.113.13.2399 · Cited by 34

Flagged first, then by citations

Research works printed but not linked: 4

Kelly, 2000, Cancer Res., 60, 957
McMahon, 2001, Cancer Res., 61, 3299
Thimmulappa, 2002, Cancer Res., 62, 5196
Bonneson, 2001, Cancer Res., 61, 6120

Sorted by citations

GLUTATHIONE TRANSFERASES
Hayes, J. D., Flanagan, J. U., & Jowsey, I. R. (2004) · The Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev.pharmtox.45.120403.095857 · Cited by 3,565
Cell Survival Responses to Environmental Stresses Via the Keap1-Nrf2-ARE Pathway
Kensler, T. W., Wakabayashi, N., & Biswal, S. (2007) · Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev.pharmtox.46.120604.141046 · Cited by 3,630
The Nrf2-antioxidant response element signaling pathway and its activation by oxidative stress
Nguyen, T., Nioi, P., & Pickett, C. B. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.r900010200 · Cited by 2,655
Heme Oxygenase-1/Carbon Monoxide: From Basic Science to Therapeutic Applications
Ryter, S. W., Alam, J., & Choi, A. M. K. (2006) · Physiological Reviews · doi:10.1152/physrev.00011.2005 · Cited by 2,342
Oxidative stress sensor Keap1 functions as an adaptor for Cul3-based E3 ligase to regulate proteasomal degradation of Nrf2
Kobayashi, A., Kang, M.-I., Okawa, H., Ohtsuji, M., Zenke, Y., Chiba, T., Igarashi, K., & Yamamoto, M. (2004) · Molecular and Cellular Biology · doi:10.1128/mcb.24.16.7130-7139.2004 · Cited by 2,224

See all 1,141

Authors: McMahon, M., Itoh, K., Yamamoto, M., & Hayes, J. D.
Affiliations: University of Dundee (GB)
University of Tsukuba (JP)
Corresponding author: McMahon, Michael
ORCID: McMahon, Michael
Itoh, Ken
Yamamoto, Masayuki
Hayes, John D.
Venue: Journal of Biological Chemistry
Publisher: Elsevier BV
Published: 2003-06
Volume: 278
Issue: 24
Pages: 21592-21600
ISSN: 0021-9258 (ISSN-L)
DOI: 10.1074/jbc.m300931200
OpenAlex: W2040114786
Cited by: 1,141
References: 54
Citations by year: 2026: 39 · 2025: 52 · 2024: 56 · 2023: 53 · 2022: 54 · 2021: 57 · 2020: 66 · 2019: 56 · 2018: 52 · 2017: 67 · 2016: 65 · 2015: 47 · 2014: 60 · 2013: 50 · 2012: 45
FWCI: 14.74
Type: journal article
Language: en
Open access: hybrid
doi.org
Licence: cc-by
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
creativecommons.org/licenses/by/4.0/ (vor, 6323 d)
Locations: Journal of Biological Chemistry (publishedVersion, cc-by)
PubMed (publishedVersion)
Discovery Research Portal (University of Dundee) (submittedVersion)
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 › Ubiquitin and proteasome pathways
Keywords: Keap1, Nrf2, proteasomal degradation, ubiquitination, oxidative stress, antioxidant response element, bZIP transcription factors, subcellular localization, sulforaphane, hepatocytes
MeSH terms: Animals, Epitopes, Antioxidants, Binding Sites, Carrier Proteins, Cell Line, Cell Nucleus, Cysteine Endopeptidases, DNA-Binding Proteins, Escherichia coli, Gene Expression Regulation, Multienzyme Complexes, Oxidation-Reduction, Plasmids, Protein Binding, RNA, Messenger, Subcellular Fractions, Sulfoxides, Thiocyanates, Time Factors, Transcription, Genetic, Transfection, Immunoblotting, Trans-Activators, Protein Structure, Tertiary, Isothiocyanates, Genes, Reporter, Oxidative Stress, COS Cells, Response Elements, Ubiquitin, Proteasome Endopeptidase Complex, NF-E2-Related Factor 2, Rats

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

Keap1-dependent Proteasomal Degradation of Transcription Factor Nrf2 Contributes to the Negative Regulation of Antioxidant Response Element-driven Gene Expression

Abstract

Overview

Integrity signals

Verification

Claims the paper makes

Claims other papers make about this one

Citations

Cites

Cited by

Related

Metadata

Record

About these checks