Keap1 represses nuclear activation of antioxidant responsive elements by Nrf2 through binding to the amino-terminal Neh2 domain
Open accessAbstract
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.
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
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?
The Neh2 domain is a redox-sensitive degron that negatively regulates Nrf2 activity and contains DLG and ETGE motifs to which Keap1 binds, as well as lysine residues targeted for ubiquitination.
“The N-terminal Neh2 domain is a redox-sensitive degron that negatively regulates Nrf2 activity and contains two highly conserved 29DLG31 and 79ETGE82 motifs to which Keap1 binds, as well as seven lysine residues that are targets for ubiquitination by the Cul3 E3 ubiquitin ligase [49,65].”
From Nrf2 and Oxidative Stress: A General Overview of Mechanisms and Implications in Human Disease (2022) · cites this paper as [49]
Nrf2 is negatively regulated by Keap1, which binds Nrf2 in the cytosol to facilitate its polyubiquitination by the Cul3 E3 ubiquitin ligase for proteasomal degradation.
“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 [49]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Molecular Cloning: A Laboratory Manual
Sambrook, J., Fritsch, E., & Maniatis, T. (1989) · UCLA - Biblioteca de Ciencias de la Salud · Cited by 133,589 · see citing works
Ashburner, M. (1989) · Cold Spring Harbor Laboratory eBooks · Cited by 6,739 · see citing works
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 · see citing works
Hayes, J. D., & Pulford, D. J. (1995) · Critical Reviews in Biochemistry and Molecular Biology · doi:10.3109/10409239509083491 · Cited by 3,471 · see citing works
Dietary Carcinogens and Anticarcinogens
Ames, B. N. (1983) · Science · doi:10.1126/science.6351251 · Cited by 2,969 · see citing works
pEF-BOS, a powerful mammalian expression vector
Mizushima, S., & Nagata, S. (1990) · Nucleic Acids Research · doi:10.1093/nar/18.17.5322 · Cited by 1,632 · see citing works
Moi, P., Chan, K., Asunis, I., Cao, A., & Kan, Y. W. (1994) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.91.21.9926 · Cited by 1,607 · see citing works
Rushmore, T. H., Morton, M. R., & Pickett, C. B. (1991) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)99004-6 · Cited by 1,464 · see citing works
Carcinogenesis by chemicals: an overview--G. H. A. Clowes memorial lecture.
MILLER, J. A. (1970) · PubMed · Cited by 1,453 · see citing works
Metabolic activation of benzo(a)pyrene proceeds by a diol-epoxide
Sims, P. H., Grover, P. L., Swaisland, A. J., Pal, K., & Hewer, A. J. (1974) · Nature · doi:10.1038/252326a0 · Cited by 1,134 · see citing works
The complete DNA sequence of vaccinia virus
Goebel, S. J., Johnson, G. P., Perkus, M. E., Davis, S. W., Winslow, J. P., & Paoletti, E. (1990) · Virology · doi:10.1016/0042-6822(90)90294-2 · Cited by 850 · see citing works
The POZ domain: a conserved protein-protein interaction motif.Preprint
Bardwell, V. J., & Treisman, R. (1994) · Genes & Development · doi:10.1101/gad.8.14.1664 · Cited by 749 · see citing works
A new class of yeast transcriptional activators.
Ma, J., & Ptashne, M. (1987) · Cell · doi:10.1016/0092-8674(87)90015-8 · Cited by 660 · see citing works
Friling, R. S., Bensimon, A., Tichauer, Y., & Daniel, V. (1990) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.87.16.6258 · Cited by 475 · see citing works
Regulation of transcription by dimerization of erythroid factor NF-E2 p45 with small Maf proteins
Igarashi, K., Kataokat, K., Itoh, K., Hayashi, N., Nishizawa, M., & Yamamoto, M. (1994) · Nature · doi:10.1038/367568a0 · Cited by 444 · see citing works
Self-citationKelch encodes a component of intercellular bridges in Drosophila egg chambers
Xue, F. (1993) · Cell · doi:10.1016/0092-8674(93)90397-9 · Cited by 440 · see citing works
Itoh, K., Igarashi, K., Hayashi, N., Nishizawa, M., & Yamamoto, M. P. (1995) · Molecular and Cellular Biology · doi:10.1128/mcb.15.8.4184 · Cited by 438 · see citing works
Self-citationKataoka, K., Noda, M., & Nishizawa, M. (1994) · Molecular and Cellular Biology · doi:10.1128/mcb.14.1.700 · Cited by 436 · see citing works
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 · see citing works
Continuous tissue culture cell lines derived from chemically induced tumors of Japanese quail
Moscovici, C., Moscovici, M. G., Jimenez, H., Lai, M. M. C., Hayman, M. J., & Vogt, P. K. (1977) · Cell · doi:10.1016/0092-8674(77)90320-8 · Cited by 402 · see citing works
Albagli, O., Dhordain, P., Deweindt, C., Lecocq, G., & Leprince, D. (1995) · PubMed · Cited by 377 · see citing works
Robbins, D. J., Nybakken, K. E., Kobayashi, R., Sisson, J. C., Bishop, J. M., & Thérond, P. P. (1997) · Cell · doi:10.1016/s0092-8674(00)80331-1 · Cited by 371 · see citing works
Crystal Structure of a Free Radical Enzyme, Galactose Oxidase
Ito, N., Phillips, S. E. V., Yadav, K. D. S., & Knowles, P. F. (1994) · Journal of Molecular Biology · doi:10.1006/jmbi.1994.1335 · Cited by 354 · see citing works
Costal2, a Novel Kinesin-Related Protein in the Hedgehog Signaling Pathway
Sisson, J. C., Ho, K. S., Suyama, K. L., & Scott, M. P. (1997) · Cell · doi:10.1016/s0092-8674(00)80332-3 · Cited by 330 · see citing works
Developmental regulation of β-globin gene switching
Choi, O.-R., & Engel, J. D. (1988) · Cell · doi:10.1016/0092-8674(88)90005-0 · Cited by 308 · see citing works
Self-citationInhibitors of Chemical Carcinogenesis
Wattenberg, L. W. (1978) · Advances in cancer research · doi:10.1016/s0065-230x(08)60088-3 · Cited by 303 · see citing works
Motohashi, H. (1997) · Nucleic Acids Research · doi:10.1093/nar/25.15.2953 · Cited by 282 · see citing works
The Maf transcription factors: regulators of differentiation
Blank, V., & Andrews, N. C. (1997) · Trends in Biochemical Sciences · doi:10.1016/s0968-0004(97)01105-5 · Cited by 276 · see citing works
The electrophile counterattack response: Protection against neoplasia and toxicity
Prestera, T., Zhang, Y., Spencer, S. R., Wilczak, C. A., & Talalay, P. (1993) · Advances in Enzyme Regulation · doi:10.1016/0065-2571(93)90024-8 · Cited by 256 · see citing works
The maternal gene skn-1 encodes a protein that is distributed unequally in early C. elegans embryos
Bowerman, B. A., Draper, B. W., Mello, C. C., & Priess, J. R. (1993) · Cell · doi:10.1016/0092-8674(93)80046-h · Cited by 251 · see citing works
Alam, J., Camhi, S. L., & Choi, A. M. K. (1995) · Journal of Biological Chemistry · doi:10.1074/jbc.270.20.11977 · Cited by 219 · see citing works
Pheromone Response in Yeast: Association of Bem1p with Proteins of the MAP Kinase Cascade and Actin
Leeuw, T., Fourest‐Lieuvin, A., Wu, C., Chenevert, J. M., Clark, K., Whiteway, M. S., Thomas, D. Y., & Leberer, E. (1995) · Science · doi:10.1126/science.270.5239.1210 · Cited by 204 · see citing works
Buetler, T. M., Gallagher, E. P., Wang, C. H., Stahl, D., Hayes, J. D., & Eaton, D. L. (1995) · Toxicology and Applied Pharmacology · doi:10.1006/taap.1995.1207 · Cited by 184 · see citing works
Beug, H., Doederlein, G., Freudenstein, C., & Graf, T. (1982) · Journal of Cellular Physiology · doi:10.1002/jcp.1041130427 · Cited by 179 · see citing works
Drosophila kelch motif is derived from a common enzyme fold
Peer Bork, B., & Doolittle, R. F. (1994) · Journal of Molecular Biology · doi:10.1016/0022-2836(94)90056-6 · Cited by 177 · see citing works
Dietary Carcinogens and Anti-Carcinogens
Ames, B. N. (1984) · Journal of Toxicology Clinical Toxicology · doi:10.3109/15563658408992561 · Cited by 154 · see citing works
Kataoka, K., Noda, M., & Nishizawa, M. (1994) · Molecular and Cellular Biology · doi:10.1128/mcb.14.1.700-712.1994 · Cited by 147 · see citing works
Natsume, T., Koide, T., Yokota, S., Hirayoshi, K., & Nagata, K. (1994) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)47412-1 · Cited by 143 · see citing works
Bannai, S. (1984) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(17)43371-0 · Cited by 141 · see citing works
Toki, T., Itoh, J., Kitazawa, J., Arai, K., Hatakeyama, K., Akasaka, J.-I., Igarashi, K., Nomura, N., Yokoyama, M., Yamamoto, M. P., et al. (1997) · Oncogene · doi:10.1038/sj.onc.1201024 · Cited by 116 · see citing works
Self-citationPrimiano, T., Sutter, T. R., & Kensler, T. W. (1996) · Advances in pharmacology · doi:10.1016/s1054-3589(08)60989-8 · Cited by 112 · see citing works
Hernandez, M., Andrés-Barquin, P. J., Martı́nez, S., Bulfone, A., Rubenstein, J. L. R., & Israel, M. A. (1997) · Journal of Neuroscience · doi:10.1523/jneurosci.17-09-03038.1997 · Cited by 97 · see citing works
cDNA Cloning of Murine Nrf 2 Gene, Coding for a p45 NF-E2-Related Transcription Factor
Chui, D. H. K., Tang, W. Z., & Orkin, S. (1995) · Biochemical and Biophysical Research Communications · doi:10.1006/bbrc.1995.1467 · Cited by 67 · see citing works
Flagged first, then by citations
1 of the 46 references couldn’t be matched to a known paper.
Cited by
Sorted by citations
Role of nrf2 in oxidative stress and toxicity
Ma, Q. (2013) · Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev-pharmtox-011112-140320 · Cited by 4,903 · see citing works
Reactive Oxygen Species in Inflammation and Tissue Injury
Mittal, M., Siddiqui, M. R., Tran, K., Reddy, S. P., & Malik, A. B. (2014) · Antioxidants & Redox Signaling · doi:10.1089/ars.2012.5149 · Cited by 4,897 · see citing works
Reactive oxygen species (ROS) homeostasis and redox regulation in cellular signaling
Ray, P. D., Huang, B.-W., & Tsuji, Y. (2012) · Cellular Signalling · doi:10.1016/j.cellsig.2012.01.008 · Cited by 4,373 · see citing works
ROS as signalling molecules: Mechanisms that generate specificity in ROS homeostasis
D'Autréaux, B., & Toledano, M. B. (2007) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2256 · Cited by 3,642 · see citing works
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 · see citing works
Self-citationCancer chemoprevention with dietary phytochemicals
Surh, Y.-J. (2003) · Nature reviews. Cancer · doi:10.1038/nrc1189 · Cited by 2,955 · see citing works
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 · see citing works
Glutathione: overview of its protective roles, measurement, and biosynthesis
Forman, H. J., Zhang, H., & Rinna, A. (2009) · Molecular Aspects of Medicine · doi:10.1016/j.mam.2008.08.006 · Cited by 2,636 · see citing works
Role of Oxidative Modifications in Atherosclerosis
Stocker, R., & Keaney, J. F. (2004) · Physiological Reviews · doi:10.1152/physrev.00047.2003 · Cited by 2,611 · see citing works
Komatsu, M., Kurokawa, H., Waguri, S., Taguchi, K., Kobayashi, A., Ichimura, Y., Sou, Y., Ueno, I., Sakamoto, A., Tong, K. I., et al. (2010) · Nature Cell Biology · doi:10.1038/ncb2021 · Cited by 2,418 · see citing works
Self-citationOncogene-induced Nrf2 transcription promotes ROS detoxification and tumorigenesis
DeNicola, G. M., Karreth, F. A., Humpton, T. J., Gopinathan, A., Wei, C., Frese, K., Mangal, D., Yu, K. H., Yeo, C. J., Calhoun, E. S., et al. (2011) · Nature · doi:10.1038/nature10189 · Cited by 2,277 · see citing works
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 2,308 · see citing works
Transcriptional Regulation by Nrf2
Tonelli, C., Chio, I. I. C., & Tuveson, D. A. (2017) · Antioxidants and Redox Signaling · doi:10.1089/ars.2017.7342 · Cited by 2,206 · see citing works
A molecular marker of artemisinin-resistant Plasmodium falciparum malaria
Ariey, F., Witkowski, B., Amaratunga, C., Beghain, J., Langlois, A.-C., Khim, N., Kim, S., Duru, V., Bouchier, C., Ma, L., et al. (2013) · Nature · doi:10.1038/nature12876 · Cited by 2,099 · see citing works
The importance of glutathione in human disease
Townsend, D. M., Tew, K. D., & Tapiero, H. (2003) · Biomedicine & Pharmacotherapy · doi:10.1016/s0753-3322(03)00043-x · Cited by 2,009 · see citing works
The KEAP1-NRF2 system: a thiol-based sensor-effector apparatus for maintaining redox homeostasis
Yamamoto, M., Kensler, T. W., & Motohashi, H. (2018) · Physiological Reviews · doi:10.1152/physrev.00023.2017 · Cited by 1,968 · see citing works
Self-citationDinkova-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 · see citing works
Self-citationNrf2 suppresses macrophage inflammatory response by blocking proinflammatory cytokine transcription
Kobayashi, E. H., Suzuki, T., Funayama, R., Nagashima, T., Hayashi, M., Sekine, H., Tanaka, N., Moriguchi, T., Motohashi, H., Nakayama, K., et al. (2016) · Nature Communications · doi:10.1038/ncomms11624 · Cited by 1,878 · see citing works
Self-citationRedox regulation of cell survival
Trachootham, D., Lu, W., Ogasawara, M. A., Valle, N. R.-D., & Huang, P. (2008) · Antioxidants & Redox Signaling · doi:10.1089/ars.2007.1957 · Cited by 1,781 · see citing works
Nrf2–Keap1 defines a physiologically important stress response mechanism
Motohashi, H., & Yamamoto, M. (2004) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2004.09.003 · Cited by 1,725 · see citing works
Self-citationNRF2 and the Hallmarks of Cancer
Rojo de la Vega, M., Chapman, E., & Zhang, D. D. (2018) · Cancer Cell · doi:10.1016/j.ccell.2018.03.022 · Cited by 1,672 · see citing works
Nrf2:INrf2 (Keap1) signaling in oxidative stress
Kaspar, J. W., Niture, S. K., & Jaiswal, A. K. (2009) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2009.07.035 · Cited by 1,646 · see citing works
The Molecular Mechanisms Regulating the KEAP1-NRF2 Pathway
Baird, L., & Yamamoto, M. P. (2020) · Molecular and Cellular Biology · doi:10.1128/mcb.00099-20 · Cited by 1,600 · see citing works
Self-citationHayes, J. D., & McLellan, L. I. (1999) · Free Radical Research · doi:10.1080/10715769900300851 · Cited by 1,528 · see citing works
Chalcone: A Privileged Structure in Medicinal Chemistry
Zhuang, C., Zhang, W., Sheng, C., Zhang, W., Xing, C., & Miao, Z. (2017) · Chemical Reviews · doi:10.1021/acs.chemrev.7b00020 · Cited by 1,486 · see citing works
Zhang, D. D., & Hannink, M. (2003) · Molecular and Cellular Biology · doi:10.1128/mcb.23.22.8137-8151.2003 · Cited by 1,480 · see citing works
Therapeutic targeting of the NRF2 and KEAP1 partnership in chronic diseases
Cuadrado, A., Rojo, A. I., Wells, G., Hayes, J. D., Cousin, S. P., Rumsey, W. L., Attucks, O. C., Franklin, S., Levonen, A., Kensler, T. W., et al. (2019) · Nature Reviews Drug Discovery · doi:10.1038/s41573-018-0008-x · Cited by 1,474 · see citing works
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 1,460 · see citing works
Self-citationAutophagy, mitochondria and oxidative stress: cross-talk and redox signalling.
Lee, J., Giordano, S., & Zhang, J. (2012) · Biochemical Journal · doi:10.1042/bj20111451 · Cited by 1,438 · see citing works
An Overview of Nrf2 Signaling Pathway and Its Role in Inflammation
Saha, S., Buttari, B., Panieri, E., Profumo, E., & Saso, L. (2020) · Molecules · doi:10.3390/molecules25225474 · Cited by 1,419 · see citing works
The role of oxidative stress in neurodegenerative diseases
Kim, G. H., Kim, J. E., Rhie, S. J., & Yoon, S. (2015) · Experimental Neurobiology · doi:10.5607/en.2015.24.4.325 · Cited by 1,355 · see citing works
The emerging role of the Nrf2–Keap1 signaling pathway in cancerPreprint
Jaramillo, M. C., & Zhang, D. D. (2013) · Genes & Development · doi:10.1101/gad.225680.113 · Cited by 1,304 · see citing works
Keap1 Is a Redox-Regulated Substrate Adaptor Protein for a Cul3-Dependent Ubiquitin Ligase Complex
Zhang, D. D., Lo, S., Cross, J. V., Templeton, D. J., & Hannink, M. (2004) · Molecular and Cellular Biology · doi:10.1128/mcb.24.24.10941-10953.2004 · Cited by 1,262 · see citing works
Nrf2 signaling in coordinated activation of antioxidant gene expression
Jaiswal, A. K. (2004) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2004.02.074 · Cited by 1,254 · see citing works
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 · see citing works
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 · see citing works
Dissecting molecular cross-talk between Nrf2 and NF-κB response pathways
Wardyn, J. D., Ponsford, A. H., & Sanderson, C. M. (2015) · Biochemical Society Transactions · doi:10.1042/bst20150014 · Cited by 1,200 · see citing works
4-Hydroxy-2-nonenal: a product and mediator of oxidative stress
Uchida, K. (2003) · Progress in Lipid Research · doi:10.1016/s0163-7827(03)00014-6 · Cited by 1,164 · see citing works
McMahon, M., Itoh, K., Yamamoto, M., & Hayes, J. D. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m300931200 · Cited by 1,141 · see citing works
Self-citationMasella, R., Benedetto, R. D., Varı́, R., Filesi, C., & Giovannini, C. (2005) · The Journal of Nutritional Biochemistry · doi:10.1016/j.jnutbio.2005.05.013 · Cited by 1,109 · see citing works
Nrf2 and Oxidative Stress: A General Overview of Mechanisms and Implications in Human Disease
Ngo, V., & Duennwald, M. L. (2022) · Antioxidants · doi:10.3390/antiox11122345 · Cited by 1,130 · see citing works
Ramos-Gomez, M., Kwak, M.-K., Dolan, P. M., Itoh, K., Yamamoto, M., Talalay, P., & Kensler, T. W. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.051618798 · Cited by 1,102 · see citing works
Self-citationMechanistic Studies of the Nrf2-Keap1 Signaling Pathway
Zhang, D. D. (2006) · Drug Metabolism Reviews · doi:10.1080/03602530600971974 · Cited by 1,091 · see citing works
Molecular Mechanisms Activating the Nrf2-Keap1 Pathway of Antioxidant Gene Regulation
Kobayashi, M., & Yamamoto, M. P. (2005) · Antioxidants and Redox Signaling · doi:10.1089/ars.2005.7.385 · Cited by 1,075 · see citing works
Self-citationBalogun, E. A., Hoque, M., Gong, P., Killeen, E., Green, C. J., Foresti, R., Alam, J., & Motterlini, R. (2003) · Biochemical Journal · doi:10.1042/bj20021619 · Cited by 1,038 · see citing works
Huang, H.-C., Nguyen, T., & Pickett, C. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m206911200 · Cited by 1,070 · see citing works
The cytoprotective role of the Keap1–Nrf2 pathway
Baird, L., & Dinkova‐Kostova, A. T. (2011) · Archives of Toxicology · doi:10.1007/s00204-011-0674-5 · Cited by 1,029 · see citing works
The Nrf2 cell defence pathway: Keap1-dependent and -independent mechanisms of regulation
Bryan, H. K., Olayanju, A., Goldring, C. E., & Park, B. K. (2012) · Biochemical Pharmacology · doi:10.1016/j.bcp.2012.11.016 · Cited by 1,026 · see citing works
Oxidative stress in health and disease: The therapeutic potential of Nrf2 activation
Hybertson, B. M., Gao, B., Bose, S. K., & McCord, J. M. (2011) · Molecular Aspects of Medicine · doi:10.1016/j.mam.2011.10.006 · Cited by 1,029 · see citing works
Molecular basis of the Keap1–Nrf2 system
Suzuki, T., & Yamamoto, M. (2015) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2015.06.006 · Cited by 995 · see citing works
Self-citationWakabayashi, 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 · see citing works
Self-citationThe emerging role of Nrf2 in mitochondrial function
Dinkova-Kostova, A. T., & Abramov, A. Y. (2015) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2015.04.036 · Cited by 983 · see citing works
Oxidative Stress and Oxidative Damage in Carcinogenesis
Klaunig, J. E., Kamendulis, L. M., & Hocevar, B. A. (2009) · Toxicologic Pathology · doi:10.1177/0192623309356453 · Cited by 960 · see citing works
Kobayashi, A., Kang, M.-I., Watai, Y., Tong, K. I., Shibata, T., Uchida, K., & Yamamoto, M. P. (2005) · Molecular and Cellular Biology · doi:10.1128/mcb.26.1.221-229.2006 · Cited by 933 · see citing works
Self-citationFerroptosis in cancer: from molecular mechanisms to therapeutic strategies
Zhou, Q., Meng, Y., Li, D., Yao, L., Le, J., Liu, Y., Sun, Y., Zeng, F., Chen, X., & Deng, G. (2024) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-024-01769-5 · Cited by 980 · see citing works
Curcumin—From Molecule to Biological Function
Esatbeyoglu, T., Huebbe, P., Ernst, I. M. A., Chin, D., Wagner, A. E., & Rimbach, G. H. (2012) · Angewandte Chemie International Edition · doi:10.1002/anie.201107724 · Cited by 908 · see citing works
Mruk, D., & Cheng, Y. C. (2004) · Endocrine reviews · doi:10.1210/er.2003-0022 · Cited by 614 · see citing works
Cullinan, S. B., Gordan, J. D., Jin, J., Harper, J. W., & Diehl, J. A. (2004) · Molecular and Cellular Biology · doi:10.1128/mcb.24.19.8477-8486.2004 · Cited by 986 · see citing works
Keap1-null mutation leads to postnatal lethality due to constitutive Nrf2 activation
Wakabayashi, N., Itoh, K., Wakabayashi, J., Motohashi, H., Noda, S., Takahashi, S., Imakado, S., KOTSUJI, T., Otsuka, F., Roop, D. R., et al. (2003) · Nature Genetics · doi:10.1038/ng1248 · Cited by 881 · see citing works
Self-citationNiture, S. K., Khatri, R., & Jaiswal, A. K. (2013) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2013.02.008 · Cited by 873 · see citing works
NRF2 and KEAP1 mutations: permanent activation of an adaptive response in cancer
Hayes, J. D., & McMahon, M. J. (2009) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2008.12.008 · Cited by 870 · see citing works
Dietary flavonoids: Effects on xenobiotic and carcinogen metabolism
Moon, Y. J., Wang, X., & Morris, M. E. (2005) · Toxicology in Vitro · doi:10.1016/j.tiv.2005.06.048 · Cited by 869 · see citing works
Itoh, K., Tong, K. I., & Yamamoto, M. P. (2004) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2004.02.075 · Cited by 866 · see citing works
Self-citationNrf2 enhances resistance of cancer cells to chemotherapeutic drugs, the dark side of Nrf2
Wang, X.-J., Sun, Z., Villeneuve, N. F., Zhang, S., Zhao, F., Li, Y., Chen, W., Yi, X., Zheng, W., Wondrak, G. T., et al. (2008) · Carcinogenesis · doi:10.1093/carcin/bgn095 · Cited by 839 · see citing works
Kobayashi, M., & Yamamoto, M. P. (2006) · Advances in Enzyme Regulation · doi:10.1016/j.advenzreg.2006.01.007 · Cited by 855 · see citing works
Self-citationTebay, L. E., Robertson, H., Durant, S. T., Vitale, S. R., Penning, T. M., Dinkova-Kostova, A. T., & Hayes, J. D. (2015) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2015.06.021 · Cited by 837 · see citing works
Metabolic Regulation of Hematopoietic Stem Cells in the Hypoxic Niche
Suda, T., Takubo, K., & Semenza, G. L. (2011) · Cell Stem Cell · doi:10.1016/j.stem.2011.09.010 · Cited by 844 · see citing works
ROS and redox signaling in myocardial ischemia-reperfusion injury and cardioprotection
Cadenas, S. (2018) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2018.01.024 · Cited by 819 · see citing works
Itoh, K., Wakabayashi, N., Katoh, Y., Ishii, T., O'Connor, T., & Yamamoto, M. P. (2003) · Genes to Cells · doi:10.1046/j.1365-2443.2003.00640.x · Cited by 817 · see citing works
Self-citationClements, C. M., McNally, R. S., Conti, B. J., Mak, T. W., & Ting, J. P.-Y. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0607260103 · Cited by 818 · see citing works
The Keap1–Nrf2–ARE Pathway As a Potential Preventive and Therapeutic Target: An Update
Lu, M., Ji, J., Jiang, Z., & You, Q. (2016) · Medicinal Research Reviews · doi:10.1002/med.21396 · Cited by 801 · see citing works
Oxidative stress response and Nrf2 signaling in aging
Zhang, H., Davies, K. J. A., & Forman, H. J. (2015) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2015.05.036 · Cited by 804 · see citing works
Calabrese, V., Cornelius, C., Dinkova‐Kostova, A. T., Calabrese, E. J., & Mattson, M. P. (2010) · Antioxidants and Redox Signaling · doi:10.1089/ars.2009.3074 · Cited by 803 · see citing works
Fahey, J. W., Haristoy, X., Dolan, P. M., Kensler, T. W., Scholtus, I., Stephenson, K. K., Talalay, P., & Lozniewski, A. (2002) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.112203099 · Cited by 794 · see citing works
Stress-activated cap’n’collar transcription factors in aging and human disease
Sykiotis, G. P., & Bohmann, D. (2010) · Science Signaling · doi:10.1126/scisignal.3112re3 · Cited by 776 · see citing works
Lee, J., Calkins, M. J., Chan, K., Kan, Y. W., & Johnson, J. A. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m211558200 · Cited by 783 · see citing works
Molecular mechanisms of Nrf2‐mediated antioxidant response
Li, W., & Kong, A. T. (2008) · Molecular Carcinogenesis · doi:10.1002/mc.20465 · Cited by 786 · see citing works
Reactive Oxygen Species: A Key Constituent in Cancer Survival
Kumari, S., Badana, A. K., Murali Mohan, G., Gugalavath, S., & Malla, R. R. (2018) · Biomarker Insights · doi:10.1177/1177271918755391 · Cited by 780 · see citing works
Expression of Nrf2 in Neurodegenerative Diseases
Ramsey, C. P., Glass, C. A., Montgomery, M. B., Lindl, K. A., Ritson, G. P., Chia, L. A., Hamilton, R. L., Chu, C. T., & Jordan-Sciutto, K. L. (2007) · Journal of Neuropathology and Experimental Neurology · doi:10.1097/nen.0b013e31802d6da9 · Cited by 760 · see citing works
An important function of Nrf2 in combating oxidative stress: Detoxification of acetaminophen
Chan, K., Han, X.-D., & Kan, Y. W. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.081082098 · Cited by 766 · see citing works
Tong, K. I., Katoh, Y., Kusunoki, H., Itoh, K., Tanaka, T., & Yamamoto, M. (2006) · Molecular and Cellular Biology · doi:10.1128/mcb.26.8.2887-2900.2006 · Cited by 759 · see citing works
Self-citationMagesh, S., Chen, Y., & Hu, L. (2012) · Medicinal Research Reviews · doi:10.1002/med.21257 · Cited by 760 · see citing works
Furukawa, M., & Xiong, Y. (2004) · Molecular and Cellular Biology · doi:10.1128/mcb.25.1.162-171.2005 · Cited by 746 · see citing works
Cullinan, S. B., & Diehl, J. A. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m314219200 · Cited by 739 · see citing works
Structural basis for defects of Keap1 activity provoked by its point mutations in lung cancer
Padmanabhan, B., Tong, K. I., Ohta, T., Nakamura, Y., Scharlock, M., Ohtsuji, M., Kang, M.-I., Kobayashi, A., Yokoyama, S., & Yamamoto, M. (2006) · Molecular Cell · doi:10.1016/j.molcel.2006.01.013 · Cited by 735 · see citing works
Self-citationShibata, T., Ohta, T., Tong, K. I., Kokubu, A., Odogawa, R., Tsuta, K., Asamura, H., Yamamoto, M., & Hirohashi, S. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0806268105 · Cited by 728 · see citing works
Self-citationEnomoto, A. (2001) · Toxicological Sciences · doi:10.1093/toxsci/59.1.169 · Cited by 728 · see citing works
Thomas, B., & Beal, M. F. (2007) · Human Molecular Genetics · doi:10.1093/hmg/ddm159 · Cited by 748 · see citing works
SKN-1 links C. elegans mesendodermal specification to a conserved oxidative stress responsePreprint
An, J. H., & Blackwell, T. K. (2003) · Genes & Development · doi:10.1101/gad.1107803 · Cited by 722 · see citing works
Dinkova‐Kostova, A. T., & Talalay, P. (2010) · Archives of Biochemistry and Biophysics · doi:10.1016/j.abb.2010.03.019 · Cited by 726 · see citing works
Tu, W., Wang, H., Li, S., Liu, Q., & Sha, H. (2018) · Aging and Disease · doi:10.14336/ad.2018.0513 · Cited by 712 · see citing works
Forman, H. J., Davies, K. J. A., & Ursini, F. (2013) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2013.05.045 · Cited by 707 · see citing works
Martı́n, D., Rojo, A. I., Salinas, M., Díaz, R. G., Gallardo, G., Alam, J., de Galarreta, C. M. R., & Cuadrado, A. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m309660200 · Cited by 698 · see citing works
Signaling to heme oxygenase-1 and its anti-inflammatory therapeutic potential
Paine, A., Eiz‐Vesper, B., Blasczyk, R., & Immenschuh, S. (2010) · Biochemical Pharmacology · doi:10.1016/j.bcp.2010.07.014 · Cited by 698 · see citing works
Molecular basis for chemoprevention by sulforaphane: a comprehensive review
Juge, N., Mithen, R. F., & Τράκα, Μ. (2007) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-007-6484-5 · Cited by 696 · see citing works
Liu, G.-H., Qu, J., & Shen, X. (2008) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2008.01.002 · Cited by 697 · see citing works
A protective role of nuclear factor-erythroid 2-related factor-2 (Nrf2) in inflammatory disorders
Kim, J., Cha, Y., & Surh, Y. (2009) · Mutation research. Fundamental and molecular mechanisms of mutagenesis · doi:10.1016/j.mrfmmm.2009.09.007 · Cited by 686 · see citing works
Toward clinical application of the Keap1-Nrf2 pathway
Suzuki, T., Motohashi, H., & Yamamoto, M. (2013) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2013.04.005 · Cited by 680 · see citing works
Self-citationOxidative Stress in Cancer Cell Metabolism
Arfin, S., Jha, N. K., Jha, S. K., Kesari, K. K., Ruokolainen, J., Roychoudhury, S., Rathi, B., & Kumar, D. (2021) · Antioxidants · doi:10.3390/antiox10050642 · Cited by 691 · see citing works
Multitargeting by curcumin as revealed by molecular interaction studies
Gupta, S. C., Prasad, S., Kim, J. H., Patchva, S., Webb, L. J., Priyadarsini, K. I., & Aggarwal, B. B. (2011) · Natural Product Reports · doi:10.1039/c1np00051a · Cited by 671 · see citing works
- Authors
- Itoh, K., Wakabayashi, N., Katoh, Y., Ishii, T., Igarashi, K., Engel, J. D., & Yamamoto, M.
- Affiliations
- University of Tsukuba (JP)
- Northwestern University (US)
- 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
- 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
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
