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.
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?
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 [51]
The mechanism by which rapamycin increases Nrf2 levels seems to occur at the level of protein stabilization rather than increasing Nrf2 gene expression.
“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.
Cites
Hershko, A., & Ciechanover, A. (1998) · Annual Review of Biochemistry · doi:10.1146/annurev.biochem.67.1.425 · Cited by 8,840 · see citing works
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 · see citing works
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 · 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
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 1,267 · 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
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
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
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 1,134 · see citing works
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 · see citing works
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 928 · see citing works
Molecular basis of the VHL hereditary cancer syndrome
Kaelin, W. G. (2002) · Nature Reviews Cancer · doi:10.1038/nrc885 · Cited by 865 · 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
Oyake, T., Itoh, K., Motohashi, H., Hayashi, N., Hoshino, H., Nishizawa, M., Yamamoto, M. P., & Igarashi, K. (1996) · Molecular and Cellular Biology · doi:10.1128/mcb.16.11.6083 · Cited by 656 · see citing works
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 · see citing works
Levonen, A., Landar, A. L., Ramachandran, A., CEASER, E. K., Dickinson, D. A., Zanoni, G., Morrow, J. D., & Darley-Usmar, V. M. (2004) · Biochemical Journal · doi:10.1042/bj20031049 · Cited by 559 · see citing works
Kang, M.-I., Kobayashi, A., Wakabayashi, N., Kim, S.-G., & Yamamoto, M. P. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0308347100 · Cited by 536 · see citing works
Xu, L., Yue, W., Reboul, J., Vaglio, P., Shin, T.-H., Vidal, M., Elledge, S. J., & Harper, J. W. (2003) · Nature · doi:10.1038/nature01985 · Cited by 497 · see citing works
Stewart, D., Killeen, E., Naquin, R., Alam, S., & Alam, J. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m209195200 · Cited by 463 · see citing works
Targeting of protein ubiquitination by BTB–Cullin 3–Roc1 ubiquitin ligases
Furukawa, M., He, Y. J., Borchers, C. H., & Xiong, Y. (2003) · Nature Cell Biology · doi:10.1038/ncb1056 · Cited by 459 · see citing works
The BTB protein MEL-26 is a substrate-specific adaptor of the CUL-3 ubiquitin-ligase
Pintard, L., Willis, J. H., Willems, A. R., Johnson, J.-L., Srayko, M., Kurz, T., Luke-Glaser, S., Mains, P. E., Tyers, M., Bowerman, B. A., et al. (2003) · Nature · doi:10.1038/nature01959 · Cited by 431 · see citing works
Cope, G. A., & Deshaies, R. J. (2003) · Cell · doi:10.1016/s0092-8674(03)00722-0 · Cited by 409 · see citing works
Cullin-3 targets cyclin E for ubiquitination and controls S phase in mammalian cellsPreprint
Singer, J. D., Gurian-West, M., Clurman, B. E., & Roberts, J. M. (1999) · Genes & Development · doi:10.1101/gad.13.18.2375 · Cited by 404 · see citing works
Ubiquitin Enters the New Millennium
Pickart, C. M. (2001) · Molecular Cell · doi:10.1016/s1097-2765(01)00347-1 · Cited by 393 · see citing works
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 · see citing works
Regulatory mechanisms of cellular response to oxidative stress
Itoh, K., Ishii, T., Wakabayashi, N., & Yamamoto, M. P. (1999) · Free Radical Research · doi:10.1080/10715769900300881 · Cited by 349 · see citing works
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 · see citing works
BTB/POZ Domain Proteins Are Putative Substrate Adaptors for Cullin 3 Ubiquitin Ligases
Geyer, R. K., Wee, S., Anderson, S., Yates, J. R., & Wolf, D. A. (2003) · Molecular Cell · doi:10.1016/s1097-2765(03)00341-1 · Cited by 339 · see citing works
Hayes, J. D., Chanas, S. A., Henderson, C. J., McMahon, M. J., Sun, C., Moffat, G. J., Wolf, C. R., & Yamamoto, M. P. (2000) · Biochemical Society Transactions · doi:10.1042/bst0280033 · Cited by 321 · see citing works
Covalent modification of all members of human cullin family proteins by NEDD8
Hori, T., Osaka, F., Chiba, T., Miyamoto, C., Okabayashi, K., Shimbara, N., Kato, S., & Tanaka, K. (1999) · Oncogene · doi:10.1038/sj.onc.1203093 · Cited by 291 · see citing works
The COP9 signalosome: an assembly and maintenance platform for cullin ubiquitin ligases?
Wolf, D. A., Zhou, C., & Wee, S. (2003) · Nature Cell Biology · doi:10.1038/ncb1203-1029 · Cited by 191 · see citing works
Pintard, L., Kurz, T., Luke-Glaser, S., Willis, J. H., Peter, M., & Bowerman, B. A. (2003) · Current Biology · doi:10.1016/s0960-9822(03)00336-1 · Cited by 178 · see citing works
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 · see citing works
Flagged first, then by citations
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
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
Targeting oxidative stress in disease: Promise and limitations of antioxidant therapy
Forman, H. J., & Zhang, H. (2021) · Nature Reviews Drug Discovery · doi:10.1038/s41573-021-00233-1 · Cited by 2,900 · 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
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 2,422 · 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
The PI3K–AKT network at the interface of oncogenic signalling and cancer metabolism
Hoxhaj, G., & Manning, B. D. (2020) · Nature Reviews Cancer · doi:10.1038/s41568-019-0216-7 · Cited by 2,137 · see citing works
An inhibitor of NEDD8-activating enzyme as a new approach to treat cancer
Soucy, T. A., Smith, P. G., Milhollen, M. A., Berger, A. J., Gavin, J. M., Adhikari, S., Brownell, J. E., Burke, K. E., Cardin, D. P., Critchley, S., et al. (2009) · Nature · doi:10.1038/nature07884 · Cited by 1,990 · 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
Nrf2 signaling pathway: pivotal roles in inflammation
Ahmed, S. M. U., Luo, L., Namani, A., Wang, X. J., & Tang, X. (2017) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2016.11.005 · Cited by 1,794 · see citing works
Redox 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
NRF2 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
Toxicity Testing in the 21st Century: A Vision and a Strategy
Krewski, D. R., Acosta, D., Andersen, M. E., Anderson, H. A., Bailar, J. C., Boekelheide, K., Brent, R., Charnley, G., Cheung, V. G., Green, S., et al. (2010) · Journal of Toxicology and Environmental Health Part B · doi:10.1080/10937404.2010.483176 · Cited by 1,696 · 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
Jain, A., Lamark, T., Sjøttem, E., Bowitz Larsen, K., Atesoh Awuh, J., Øvervatn, A., McMahon, M., Hayes, J. D., & Johansen, T. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.118976 · Cited by 1,472 · see citing works
Molecular mechanisms of the Keap1-Nrf2 pathway in stress response and cancer evolution
Taguchi, K., Motohashi, H., & Yamamoto, M. (2011) · Genes to Cells · doi:10.1111/j.1365-2443.2010.01473.x · Cited by 1,478 · 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
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
Reactive oxygen species and mitochondria: A nexus of cellular homeostasis
Dunn, J. D., Álvarez, L., Zhang, X., & Soldati, T. (2015) · Redox Biology · doi:10.1016/j.redox.2015.09.005 · Cited by 1,199 · see citing works
Somatic mutant clones colonize the human esophagus with age
Martincorena, I., Fowler, J. C., Wabik, A., Lawson, A. R. J., Abascal, F., Hall, M. W. J., Cagan, A., Murai, K., Mahbubani, K., Stratton, M. R., et al. (2018) · Science · doi:10.1126/science.aau3879 · Cited by 1,113 · 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
Mechanistic 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
Antioxidant responses and cellular adjustments to oxidative stress
Espinosa-Diez, C., Miguel, V., Mennerich, D., Kietzmann, T., Sánchez-Pérez, P., Cadenas, S., & Lamas, S. (2015) · Redox Biology · doi:10.1016/j.redox.2015.07.008 · Cited by 1,046 · 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
Dysfunctional KEAP1–NRF2 Interaction in Non-Small-Cell Lung Cancer
Singh, A., Misra, V., Thimmulappa, R. K., Lee, H., Ames, S., Hoque, M. O., Herman, J. G., Baylin, S. B., Sidransky, D., Gabrielson, E., et al. (2006) · PLoS Medicine · doi:10.1371/journal.pmed.0030420 · Cited by 1,060 · 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
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
The 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
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
Ferroptosis 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
Niture, 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
Nrf2 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
Hydrogen peroxide sensing, signaling and regulation of transcription factors
Marinho, H. S., Real, C., Cyrne, L., Soares, H., & Antunes, F. (2014) · Redox Biology · doi:10.1016/j.redox.2014.02.006 · Cited by 851 · see citing works
Tebay, 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
The Role of Sirtuins in Antioxidant and Redox Signaling
Singh, C. K., Chhabra, G., Ndiaye, M. A., Garcia‐Peterson, L. M., Mack, N. J., & Ahmad, N. (2017) · Antioxidants and Redox Signaling · doi:10.1089/ars.2017.7290 · Cited by 812 · see citing works
The impact of oxidative stress and inflammation on RPE degeneration in non-neovascular AMD
Datta, S., Cano, M., Ebrahimi, K. B., Wang, L., & Handa, J. T. (2017) · Progress in Retinal and Eye Research · doi:10.1016/j.preteyeres.2017.03.002 · Cited by 814 · see citing works
Clements, 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 807 · 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
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
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
Redox-based regulation of signal transduction: principles, pitfalls, and promises
Janssen-Heininger, Y. M. W., Mossman, B. T., Heintz, N. H., Forman, H. J., Kalyanaraman, B., Finkel, T., Stamler, J. S., Rhee, S. G., & van der Vliet, A. (2008) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2008.03.011 · Cited by 784 · see citing works
Rada, P., Rojo, A. I., Chowdhry, S., McMahon, M., Hayes, J. D., & Cuadrado, A. (2011) · Molecular and Cellular Biology · doi:10.1128/mcb.01204-10 · Cited by 759 · 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
Magesh, 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
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
Activation of Nrf2-antioxidant signaling attenuates NFκB-inflammatory response and elicits apoptosis
Li, W., Khor, T. O., Xu, C., Shen, G., Jeong, W.-S., Yu, S., & Kong, A.-N. (2008) · Biochemical Pharmacology · doi:10.1016/j.bcp.2008.07.017 · Cited by 738 · see citing works
Shibata, 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
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
Sequence and structural analysis of BTB domain proteins
Stogios, P. J., Downs, G. S., Jauhal, J. J., Nandra, S. K., & Privé, G. G. (2005) · Genome Biology · doi:10.1186/gb-2005-6-10-r82 · Cited by 694 · 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
Buendía, I., Michalska, P., Navarro, E., Gameiro‐Ros, I., Egea, J., & Leon, R. M. (2015) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2015.11.003 · Cited by 683 · 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
Brusatol enhances the efficacy of chemotherapy by inhibiting the Nrf2-mediated defense mechanism
Ren, D., Villeneuve, N. F., Jiang, T., Wu, T., Lau, A., Toppin, H. A., & Zhang, D. D. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1014275108 · Cited by 673 · see citing works
Direct Interaction between Nrf2 and p21Cip1/WAF1 Upregulates the Nrf2-Mediated Antioxidant Response
Chen, W., Sun, Z., Wang, X.-J., Jiang, T., Huang, Z., Fang, D., & Zhang, D. D. (2009) · Molecular Cell · doi:10.1016/j.molcel.2009.04.029 · Cited by 638 · see citing works
Chowdhry, S., Zhang, Y., McMahon, M., Sutherland, C., Cuadrado, A., & Hayes, J. D. (2013) · Oncogene · doi:10.1038/onc.2012.388 · Cited by 657 · see citing works
LAU, A., VILLENEUVE, N., Sun, Z., Wong, P. K., & Zhang, D. (2008) · Pharmacological Research · doi:10.1016/j.phrs.2008.09.003 · Cited by 645 · see citing works
The double-edged roles of ROS in cancer prevention and therapy
Wang, Y., Qi, H., Liu, Y., Duan, C., Liu, X., Xia, T., Chen, D., Piao, H., & Liu, H. (2021) · Theranostics · doi:10.7150/thno.56747 · Cited by 646 · see citing works
Kobayashi, M., Li, L., Iwamoto, N., Nakajima‐Takagi, Y., Kaneko, H., Nakayama, Y., Eguchi, M., Wada, Y., Kumagai, Y., & Yamamoto, M. P. (2008) · Molecular and Cellular Biology · doi:10.1128/mcb.01080-08 · Cited by 641 · see citing works
The Dual Roles of NRF2 in Cancer
Menegon, S., Columbano, A., & Giordano, S. (2016) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2016.05.002 · Cited by 633 · see citing works
Loss of Keap1 Function Activates Nrf2 and Provides Advantages for Lung Cancer Cell Growth
Ohta, T., Iijima, K., Miyamoto, M., Nakahara, I., Tanaka, H., Ohtsuji, M., Suzuki, T., Kobayashi, A., Yokota, J., Sakiyama, T., et al. (2008) · Cancer Research · doi:10.1158/0008-5472.can-07-5003 · Cited by 630 · see citing works
Emerging roles of Nrf2 and phase II antioxidant enzymes in neuroprotection
Zhang, M., An, C., Gao, Y., Leak, R. K., Chen, J., & Zhang, F. (2012) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2012.09.003 · Cited by 622 · see citing works
Structural basis of Keap1 interactions with Nrf2
Canning, P., Sorrell, F. J., & Bullock, A. N. (2015) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2015.05.034 · Cited by 605 · see citing works
Structure of the Keap1:Nrf2 interface provides mechanistic insight into Nrf2 signaling
Lo, S., Li, X., Henzl, M. T., Beamer, L. J., & Hannink, M. (2006) · The EMBO Journal · doi:10.1038/sj.emboj.7601243 · Cited by 604 · see citing works
When NRF2 Talks, Who's Listening?
Wakabayashi, N., Slocum, S. L., Skoko, J. J., Shin, S., & Kensler, T. W. (2010) · Antioxidants & Redox Signaling · doi:10.1089/ars.2010.3216 · Cited by 595 · see citing works
The Two Faces of Reactive Oxygen Species in Cancer
Reczek, C. R., & Chandel, N. S. (2017) · Annual Review of Cancer Biology · doi:10.1146/annurev-cancerbio-041916-065808 · Cited by 602 · see citing works
“Normally, NRF2 is targeted for proteasomal degradation through its interaction with the cytoplasmic protein Kelchlike ECH-associated protein 1 (KEAP1) and the Cul3-based E3 ubiquitin ligase (Ishii et al. 2000, Itoh et al. 1999, Kobayashi et al. 2004).”
BackgroundBasic Principles and Emerging Concepts in the Redox Control of Transcription Factors
Brigelius-Flohé, R., & Flohé, L. (2011) · Antioxidants and Redox Signaling · doi:10.1089/ars.2010.3534 · Cited by 577 · see citing works
Coordination of ER and oxidative stress signaling: The PERK/Nrf2 signaling pathway
Cullinan, S. B., & Diehl, J. A. (2006) · The International Journal of Biochemistry & Cell Biology · doi:10.1016/j.biocel.2005.09.018 · Cited by 554 · see citing works
Cancer Metabolism: Phenotype, Signaling and Therapeutic Targets
Park, J. H., Pyun, W. Y., & Park, H. W. (2020) · Cells · doi:10.3390/cells9102308 · Cited by 558 · see citing works
Cancer Chemoprevention Mechanisms Mediated Through the Keap1–Nrf2 Pathway
Hayes, J. D., McMahon, M. J., Chowdhry, S., & Dinkova‐Kostova, A. T. (2010) · Antioxidants and Redox Signaling · doi:10.1089/ars.2010.3221 · Cited by 540 · see citing works
The KEAP1–NRF2 System in Cancer
Taguchi, K., & Yamamoto, M. (2017) · Frontiers in Oncology · doi:10.3389/fonc.2017.00085 · Cited by 527 · see citing works
Modulating NRF2 in Disease: Timing Is Everything
Dodson, M. B., de la Vega, M. R., Cholanians, A. B., Schmidlin, C. J., Chapman, E., & Zhang, D. D. (2018) · The Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev-pharmtox-010818-021856 · Cited by 540 · see citing works
Mechanisms of mitochondrial dysfunction and their impact on age-related macular degeneration
Kaarniranta, K., Uusitalo, H. M. T., Błasiak, J., Felszeghy, S., Kannan, R., Kauppinen, A., Salminen, A., Sinha, D., & Ferrington, D. A. (2020) · Progress in Retinal and Eye Research · doi:10.1016/j.preteyeres.2020.100858 · Cited by 528 · see citing works
Salazar‐Roa, M., Rojo, A. I., Velasco, D., de Sagarra, R. M., & Cuadrado, A. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m513737200 · Cited by 523 · see citing works
PROTACs: An Emerging Therapeutic Modality in Precision Medicine
Nalawansha, D. A., & Crews, C. M. (2020) · Cell chemical biology · doi:10.1016/j.chembiol.2020.07.020 · Cited by 514 · see citing works
Physiological Significance of Reactive Cysteine Residues of Keap1 in Determining Nrf2 Activity
Yamamoto, T., Suzuki, T., Kobayashi, A., Wakabayashi, J., Maher, J. M., Motohashi, H., & Yamamoto, M. P. (2008) · Molecular and Cellular Biology · doi:10.1128/mcb.01704-07 · Cited by 515 · see citing works
Nrf2/Keap1/ARE signaling: Towards specific regulation
Ulasov, A. V., Rosenkranz, A. A., Georgiev, G. P., & Sobolev, A. S. (2021) · Life Sciences · doi:10.1016/j.lfs.2021.120111 · Cited by 520 · see citing works
Discovery of the Negative Regulator of Nrf2, Keap1: A Historical Overview
Itoh, K., Mimura, J., & Yamamoto, M. P. (2010) · Antioxidants and Redox Signaling · doi:10.1089/ars.2010.3222 · Cited by 513 · see citing works
Pollier, J., & Goossens, A. (2012) · Phytochemistry · doi:10.1016/j.phytochem.2011.12.022 · Cited by 505 · see citing works
Targeting antioxidants for cancer therapy
Glasauer, A., & Chandel, N. S. (2014) · Biochemical Pharmacology · doi:10.1016/j.bcp.2014.07.017 · Cited by 502 · see citing works
Regulation of Signal Transduction by Reactive Oxygen Species in the Cardiovascular System
Brown, D., & Griendling, K. K. (2015) · Circulation Research · doi:10.1161/circresaha.116.303584 · Cited by 498 · see citing works
McMahon, M. J., Thomas, N., Itoh, K., Yamamoto, M. P., & Hayes, J. D. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m601119200 · Cited by 489 · see citing works
Nrf2: friend or foe for chemoprevention?
Kensler, T. W., & Wakabayashi, N. (2009) · Carcinogenesis · doi:10.1093/carcin/bgp231 · Cited by 487 · see citing works
Keap1 degradation by autophagy for the maintenance of redox homeostasis
Taguchi, K., Fujikawa, N., Komatsu, M., Ishii, T., Unno, M., Akaike, T., Motohashi, H., & Yamamoto, M. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1121572109 · Cited by 482 · see citing works
Jain, A. K., & Jaiswal, A. K. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m611336200 · Cited by 484 · see citing works
Action of Nrf2 and Keap1 in ARE-mediated NQO1 expression by quercetin
Tanigawa, S., Fujii, M., & Hou, D.-X. (2007) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2007.02.017 · Cited by 483 · see citing works
The Nrf2 System as a Potential Target for the Development of Indirect Antioxidants
Jung, K.-A., & Kwak, M. (2010) · Molecules · doi:10.3390/molecules15107266 · Cited by 476 · see citing works
Rada, P., Rojo, A. I., Evrard‐Todeschi, N., Innamorato, N. G., Cotte, A., Jaworski, T., Tobón-Velasco, J. C., Devijver, H., García‐Mayoral, M. F., LEUVEN, F. V., et al. (2012) · Molecular and Cellular Biology · doi:10.1128/mcb.00180-12 · Cited by 474 · see citing works
Nrf2 in cancers: A double‐edged sword
Wu, S., Lu, H., & Bai, Y. (2019) · Cancer Medicine · doi:10.1002/cam4.2101 · Cited by 473 · see citing works
Two-site substrate recognition model for the Keap1-Nrf2 system: A hinge and latch mechanism
Tong, K. I., Kobayashi, A., Katsuoka, F., & Yamamoto, M. (2006) · Biological Chemistry · doi:10.1515/bc.2006.164 · Cited by 473 · see citing works
Shibata, T., Kokubu, A., Gotoh, M., Ojima, H., Ohta, T., Yamamoto, M. P., & Hirohashi, S. (2008) · Gastroenterology · doi:10.1053/j.gastro.2008.06.082 · Cited by 470 · see citing works
Eggler, A. L., Liu, G., Pezzuto, J. M., van Breemen, R. B., & Mesecar, A. D. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0502402102 · Cited by 459 · see citing works
- 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
