Distinct cysteine residues in Keap1 are required for Keap1-dependent ubiquitination of Nrf2 and for stabilization of Nrf2 by chemopreventive agents and oxidative stress
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A common feature of diverse chemopreventive agents is the ability to activate expression of a genetic program that protects cells from reactive chemical species that, if left unchecked, would cause mutagenic DNA damage. The bZIP transcription factor Nrf2 has emerged as a key regulator of this cancer-preventive genetic program. Nrf2 is normally sequestered in the cytoplasm by a protein known as Keap1. Chemopreventive agents allow Nrf2 to escape from Keap1-mediated repression, although the molecular mechanism(s) responsible for activation of Nrf2 is not understood. In this report, we demonstrate that Keap1 does not passively sequester Nrf2 in the cytoplasm but actively targets Nrf2 for ubiquitination and degradation by the proteosome under basal culture conditions. We have identified two critical cysteine residues in Keap1, C273 and C288, that are required for Keap1-dependent ubiquitination of Nrf2. Both sulforaphane, a chemopreventive isothiocyanate, and oxidative stress enable Nrf2 to escape Keap1-dependent degradation, leading to stabilization of Nrf2, increased nuclear localization of Nrf2, and activation of Nrf2-dependent cancer-protective genes. We have identified a third cysteine residue in Keap1, C151, that is uniquely required for inhibition of Keap1-dependent degradation of Nrf2 by sulforaphane and oxidative stress. This cysteine residue is also required for a novel posttranslational modification to Keap1 that is induced by oxidative stress. We propose that Keap1 is a component of a novel E3 ubiquitin ligase complex that is specifically targeted for inhibition by both chemopreventive agents and oxidative stress.
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Cys273 and Cys288 are required for sensing oxidative stress under both basal and stress conditions, whereas Cys151 may be required only during oxidative stress conditions.
“Cys273 and Cys288 are required for sensing oxidative stress under both basal and stress conditions, whereas Cys151 may be required only during oxidative stress conditions [53,54].”
From Nrf2 and Oxidative Stress: A General Overview of Mechanisms and Implications in Human Disease (2022) · cites this paper as [53]
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1 retracted
Buschmann, T., Fuchs, S. Y., Lee, C.-G., Pan, Z., & Ronai, Z. A. (2000) · Cell · doi:10.1016/s0092-8674(00)80887-9 · Cited by 267 · see citing works
RetractedMechanisms Underlying Ubiquitination
Pickart, C. M. (2001) · Annual Review of Biochemistry · doi:10.1146/annurev.biochem.70.1.503 · Cited by 3,731 · see citing works
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 · see citing works
Fruit, vegetables, and cancer prevention: a review of the epidemiological evidence.
Block, G., Patterson, B. H., & Subar, A. (1992) · Nutrition and Cancer · doi:10.1080/01635589209514201 · Cited by 3,321 · 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
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
Yang, C. S., Landau, J. M., Huang, M.-T., & Newmark, H. L. (2001) · Annual Review of Nutrition · doi:10.1146/annurev.nutr.21.1.381 · Cited by 1,260 · 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
(2002) · PubMed · Cited by 1,190 · 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
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
Huang, H.-C., Nguyen, T., & Pickett, C. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m206911200 · Cited by 1,070 · see citing works
Protein ubiquitination involving an E1–E2–E3 enzyme ubiquitin thioester cascade
Scheffner, M., Nuber, U. A., & Huibregtse, J. M. (1995) · Nature · doi:10.1038/373081a0 · Cited by 1,017 · 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
A Thiol Peroxidase Is an H2O2 Receptor and Redox-Transducer in Gene Activation
Delaunay, A., Pflieger, D., Barrault, M., Vinh, J., & Tolédano, M. B. (2002) · Cell · doi:10.1016/s0092-8674(02)01048-6 · Cited by 902 · 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
Functional antioxidant responsive elements
Wasserman, W. W., & Fahl, W. E. (1997) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.94.10.5361 · Cited by 705 · see citing works
Kwak, M.-K., Wakabayashi, N., Itoh, K., Motohashi, H., Yamamoto, M. P., & Kensler, T. W. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m211898200 · Cited by 661 · see citing works
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 · 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
Phytochemicals from Cruciferous Plants Protect against Cancer by Modulating Carcinogen Metabolism
Talalay, P., & Fahey, J. W. (2001) · Journal of Nutrition · doi:10.1093/jn/131.11.3027s · Cited by 610 · see citing works
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 · see citing works
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 · see citing works
Dinkova‐Kostova, A. T., Massiah, M. A., Bozak, R. E., Hicks, R. J., & Talalay, P. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.051632198 · Cited by 594 · 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
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 · see citing works
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 · see citing works
Progress in Cancer Chemoprevention: Development of Diet-Derived Chemopreventive Agents
Kelloff, G. J., Crowell, J. A., Steele, V. E., Lubet, R. A., Malone, W. A., Boone, C. W., Kopelovich, L., Hawk, E. T., Lieberman, R., Lawrence, J. A., et al. (2000) · Journal of Nutrition · doi:10.1093/jn/130.2.467s · Cited by 441 · see citing works
Antioxidants and oxidants regulated signal transduction pathways
Owuor, E. D., & Kong, A. T. (2002) · Biochemical Pharmacology · doi:10.1016/s0006-2952(02)01137-1 · Cited by 439 · see citing works
Kwak, M., Itoh, K., Yamamoto, M. P., Sutter, T. R., & Kensler, T. W. (2001) · Molecular Medicine · doi:10.1007/bf03401947 · Cited by 357 · see citing works
Yoh, K., Itoh, K., Enomoto, A., Hirayama, A., Yamaguchi, N., Kobayashi, M., Morito, N., Kôyama, A., Yamamoto, M. P., & Takahashi, S. (2001) · Kidney International · doi:10.1046/j.1523-1755.2001.00939.x · Cited by 345 · see citing works
Yu, R., Chen, C., Mo, Y.-Y., Hebbar, V., Owuor, E. D., Tan, T., & Kong, A.-N. T. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.m004037200 · Cited by 341 · see citing works
Kwak, M.-K., Itoh, K., Yamamoto, M. P., Sutter, T. R., & Kensler, T. W. (2001) · PubMed Central · Cited by 330 · 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
Kong, A., Owuor, E. D., Yu, R., Hebbar, V., Chen, C., Hu, R., & Mandlekar, S. (2001) · Drug Metabolism Reviews · doi:10.1081/dmr-120000652 · Cited by 318 · see citing works
Chan, J. Y., & Kwong, M. (2000) · Biochimica et Biophysica Acta (BBA) - Gene Structure and Expression · doi:10.1016/s0167-4781(00)00238-4 · Cited by 317 · see citing works
Dhakshinamoorthy, S., & Jaiswal, A. K. (2001) · Oncogene · doi:10.1038/sj.onc.1204506 · Cited by 290 · see citing works
Manipulation of oxidative protein folding and PDI redox state in mammalian cells
Mezghrani, A., Fassio, A., Benham, A. M., Simmen, T., Braakman, I., & Sitia, R. (2001) · The EMBO Journal · doi:10.1093/emboj/20.22.6288 · Cited by 250 · see citing works
Lee, J., Hanson, J. M., Chu, W. A., & Johnson, J. A. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m100734200 · Cited by 227 · see citing works
Li, J., Lee, J., & Johnson, J. A. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m109380200 · Cited by 193 · see citing works
Sekhar, K. R., Yan, X. X., & Freeman, M. L. (2002) · Oncogene · doi:10.1038/sj.onc.1205905 · Cited by 139 · see citing works
Chemoprotection by Organosulfur Inducers of Phase 2 Enzymes: Dithiolethiones and Dithiins
Kensler, T. W., Curphey, T. J., Maxiutenko, Y., & Roebuck, B. D. (2000) · Drug metabolism and drug interactions · doi:10.1515/dmdi.2000.17.1-4.3 · Cited by 131 · see citing works
Crystal structure of the precursor of galactose oxidase: An unusual self-processing enzyme
Firbank, S. J., Rogers, M. S., Wilmot, C. M., Dooley, D. M., Halcrow, M. A., Knowles, P. F., McPherson, M. J., & Phillips, S. E. V. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.231463798 · Cited by 124 · see citing works
Flagged first, then by citations
Research works printed but not linked: 4
- [11]Guyton, K. Z., and T. W. Kensler. 2000. Chemoprotection by phase 2 enzyme induction, p. 54-68. In G. M. Williams and O. I. Aruoma (ed.), Molecular drug metabolism in toxicology. OICA International Ltd., London, United Kindgom.
- [34]Sambrook, J., and D. W. Russell. 2001. Molecular cloning: a laboratory manual, 3rd ed. Cold Spring Harbor Press, Cold Spring Harbor, N.Y.
- [42]Yang, C. S., J. M. Landau, M. T. Huang, and H. L. Newmark. 2001. Inhibition of carcinogenesis by dietary polyphenolic compounds. Annu. Rev. Nutr. 21:381-406. [DOI] [PubMed] [Google Scholar]
- [43]Yoh, K., K. Itoh, A. Enomoto, A. Hirayama, N. Yamaguchi, M. Kobayashi, N. Morito, A. Koyama, M. Yamamoto, and S. Takahashi. 2001. Nrf2-deficient female mice develop lupus-like autoimmune nephritis. Kidney Int. 60:1343-1353. [DOI] [PubMed] [Google Scholar]
Cited by
Sorted by citations
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
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
Oxidative Stress: An Essential Factor in the Pathogenesis of Gastrointestinal Mucosal Diseases
Bhattacharyya, A., Chattopadhyay, R., Mitra, S., & Crowe, S. E. (2014) · Physiological Reviews · doi:10.1152/physrev.00040.2012 · Cited by 2,484 · see citing works
Signal transduction by reactive oxygen species
Finkel, T. (2011) · Journal of Cell Biology · doi:10.1083/jcb.201102095 · Cited by 2,322 · see citing works
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 citing works
The Nrf2 regulatory network provides an interface between redox and intermediary metabolism
Hayes, J. D., & Dinkova‐Kostova, A. T. (2014) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2014.02.002 · Cited by 2,158 · see citing works
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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
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Yamamoto, M., Kensler, T. W., & Motohashi, H. (2018) · Physiological Reviews · doi:10.1152/physrev.00023.2017 · Cited by 1,968 · see citing works
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Mills, E. L., Ryan, D. G., Prag, H. A., Dikovskaya, D., Menon, D., Zaslona, Z., Jedrychowski, M. P., Costa, A. S. H., Higgins, M., Hams, E., et al. (2018) · Nature · doi:10.1038/nature25986 · Cited by 1,885 · see citing works
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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
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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
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Meo, S. D., Reed, T. T., Venditti, P., & Víctor, V. M. (2016) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2016/1245049 · Cited by 1,638 · see citing works
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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
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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
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Jaramillo, M. C., & Zhang, D. D. (2013) · Genes & Development · doi:10.1101/gad.225680.113 · Cited by 1,304 · see citing works
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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
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Ngo, V., & Duennwald, M. L. (2022) · Antioxidants · doi:10.3390/antiox11122345 · Cited by 1,130 · see citing works
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Zhang, D. D. (2006) · Drug Metabolism Reviews · doi:10.1080/03602530600971974 · Cited by 1,091 · see citing works
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Kobayashi, M., & Yamamoto, M. P. (2005) · Antioxidants and Redox Signaling · doi:10.1089/ars.2005.7.385 · Cited by 1,075 · see citing works
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Baird, L., & Dinkova‐Kostova, A. T. (2011) · Archives of Toxicology · doi:10.1007/s00204-011-0674-5 · Cited by 1,029 · see citing works
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Suzuki, T., & Yamamoto, M. (2015) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2015.06.006 · Cited by 995 · 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
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
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
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
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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
Kobayashi, M., & Yamamoto, M. P. (2006) · Advances in Enzyme Regulation · doi:10.1016/j.advenzreg.2006.01.007 · Cited by 855 · see citing works
Lau, A., Wang, X.-J., Zhao, F. L., Villeneuve, N. F., Wu, T., Jiang, T., Sun, Z., White, E., & Zhang, D. D. (2010) · Molecular and Cellular Biology · doi:10.1128/mcb.00248-10 · Cited by 851 · 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
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Lu, M., Ji, J., Jiang, Z., & You, Q. (2016) · Medicinal Research Reviews · doi:10.1002/med.21396 · Cited by 801 · 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
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Li, W., & Kong, A. T. (2008) · Molecular Carcinogenesis · doi:10.1002/mc.20465 · Cited by 786 · 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
Magesh, S., Chen, Y., & Hu, L. (2012) · Medicinal Research Reviews · doi:10.1002/med.21257 · Cited by 760 · see citing works
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Vomund, S., Schäfer, A., Parnham, M., Brüne, B., & Von Knethen, A. (2017) · International Journal of Molecular Sciences · doi:10.3390/ijms18122772 · Cited by 752 · see citing works
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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
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Kerins, M. J., & Ooi, A. (2017) · Antioxidants and Redox Signaling · doi:10.1089/ars.2017.7176 · Cited by 741 · 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
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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
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
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
Self-citationAmino Assets: How Amino Acids Support Immunity
Kelly, B. L., & Pearce, E. L. (2020) · Cell Metabolism · doi:10.1016/j.cmet.2020.06.010 · Cited by 653 · 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
Self-citationGureev, A. P., Shaforostova, E. A., & Popov, V. N. (2019) · Frontiers in Genetics · doi:10.3389/fgene.2019.00435 · Cited by 651 · 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
p62 links autophagy and Nrf2 signaling
Jiang, T., Harder, B. G., de la Vega, M. R., Wong, P. K., Chapman, E., & Zhang, D. D. (2015) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2015.06.014 · Cited by 642 · see citing works
Self-citationSivandzade, F., Prasad, S., Bhalerao, A., & Cucullo, L. (2019) · Redox Biology · doi:10.1016/j.redox.2018.11.017 · Cited by 639 · 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
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
The Endoplasmic Reticulum: Folding, Calcium Homeostasis, Signaling, and Redox Control
Görlach, A., Klappa, P., & Kietzmann, T. (2006) · Antioxidants and Redox Signaling · doi:10.1089/ars.2006.8.1391 · Cited by 616 · see citing works
Generation and Biological Activities of Oxidized Phospholipids
Bochkov, V. N., Oskolkova, O., Birukov, K. G., Levonen, A., Binder, C. J., & Stöckl, J. (2009) · Antioxidants and Redox Signaling · doi:10.1089/ars.2009.2597 · Cited by 611 · 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
Self-citationPiantadosi, C. A., Carraway, M. S., Babiker, A., & Suliman, H. B. (2008) · Circulation Research · doi:10.1161/01.res.0000338597.71702.ad · Cited by 580 · see citing works
Basic 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
Yang, G., Zhao, K., Ju, Y., Mani, S., Cao, Q., Puukila, S., Khaper, N., Wu, L., & Wang, R. (2012) · Antioxidants and Redox Signaling · doi:10.1089/ars.2012.4645 · Cited by 562 · see citing works
ROS in Cancer: The Burning Question
Chio, I. I. C., & Tuveson, D. A. (2017) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2017.03.004 · Cited by 532 · 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
Miao, W., Hu, L., Scrivens, P. J., & Batist, G. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m412081200 · Cited by 541 · 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
The Keap1-Nrf2 System: A Mediator between Oxidative Stress and Aging
Yu, C., & Xiao, J.-H. (2021) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2021/6635460 · Cited by 537 · 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
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
Self-citationNrf2 as a novel molecular target for chemoprevention
Lee, J., & Surh, Y. (2004) · Cancer Letters · doi:10.1016/j.canlet.2004.09.042 · 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
Neuroprotective Effect of Antioxidants in the Brain
Lee, K. H., Cha, M., & Lee, B. H. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21197152 · Cited by 527 · see citing works
Glucosinolates, isothiocyanates and human health
Τράκα, Μ., & Mithen, R. F. (2008) · Phytochemistry Reviews · doi:10.1007/s11101-008-9103-7 · Cited by 490 · 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
Na, H., & Surh, Y. (2007) · Food and Chemical Toxicology · doi:10.1016/j.fct.2007.10.006 · Cited by 486 · see citing works
Zhuang, M., Calabrese, M. F., Liu, J., Waddell, M. B., Nourse, A., Hammel, M., Miller, D. J., Walden, H., Duda, D. M., Seyedin, S. N., et al. (2009) · Molecular Cell · doi:10.1016/j.molcel.2009.09.022 · Cited by 486 · see citing works
Nutraceutical Antioxidants as Novel Neuroprotective Agents
Kelsey, N. A., Wilkins, H., & Linseman, D. A. (2010) · Molecules · doi:10.3390/molecules15117792 · Cited by 481 · 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
Nrf2 at the heart of oxidative stress and cardiac protection
Chen, Q. M., & Maltagliati, A. J. (2017) · Physiological Genomics · doi:10.1152/physiolgenomics.00041.2017 · Cited by 474 · 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
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
Inflammation-induced DNA damage, mutations and cancer
Kay, J. E., Thadhani, E., Samson, L. D., & Engelward, B. P. (2019) · DNA repair · doi:10.1016/j.dnarep.2019.102673 · Cited by 481 · see citing works
A Dual Role of Heme Oxygenase-1 in Cancer Cells
Chiang, S.-K., Chen, S., & Chang, L. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms20010039 · Cited by 466 · see citing works
Nrf2 Defends the Lung from Oxidative Stress
Cho, H., Reddy, S. P., & Kleeberger, S. R. (2006) · Antioxidants and Redox Signaling · doi:10.1089/ars.2006.8.76 · Cited by 463 · see citing works
The pathways and molecular mechanisms regulating Nrf2 activation in response to chemical stress
Nguyen, T., Yang, C. S., & Pickett, C. B. (2004) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2004.04.033 · Cited by 463 · 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
Oxeiptosis, a ROS-induced caspase-independent apoptosis-like cell-death pathway
Holze, C., Michaudel, C., Mackowiak, C., Haas, D. A., Benda, C., Hubel, P., Pennemann, F. L., Schnepf, D., Wettmarshausen, J., Braun, M., et al. (2017) · Nature Immunology · doi:10.1038/s41590-017-0013-y · Cited by 459 · see citing works
Reactive Oxygen Species in Macrophages: Sources and Targets
Canton, M., Sánchez‐Rodríguez, R., Spera, I., Venegas, F. C., Favia, M., Viola, A., & Castegna, A. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.734229 · Cited by 463 · see citing works
Li, N., Alam, J., Venkatesan, M. I., Eiguren-Fernández, A., Schmitz, D. A., Distefano, E. W., Slaughter, N., Killeen, E., Wang, X., Huang, A., et al. (2004) · The Journal of Immunology · doi:10.4049/jimmunol.173.5.3467 · Cited by 456 · see citing works
Crosstalk between Oxidative Stress and SIRT1: Impact on the Aging Process
Salminen, A., Kaarniranta, K., & Kauppinen, A. (2013) · International Journal of Molecular Sciences · doi:10.3390/ijms14023834 · Cited by 457 · see citing works
The complexity of the Nrf2 pathway: beyond the antioxidant response
Huang, Y. S., Li, W., Su, Z., & Kong, A. T. (2015) · The Journal of Nutritional Biochemistry · doi:10.1016/j.jnutbio.2015.08.001 · Cited by 449 · see citing works
McMahon, M. J., Lamont, D. J., Beattie, K. A., & Hayes, J. D. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1007387107 · Cited by 445 · see citing works
The Nrf2/ARE Pathway as a Potential Therapeutic Target in Neurodegenerative Disease
Calkins, M. J., Johnson, D. A., Townsend, J. A., Vargas, M. R., Dowell, J. A., Williamson, T. P., Kraft, A. D., Lee, J., Li, J., & Johnson, J. A. (2008) · Antioxidants and Redox Signaling · doi:10.1089/ars.2008.2242 · Cited by 440 · see citing works
Redox regulation by NRF2 in aging and disease
Schmidlin, C. J., Dodson, M. B., Madhavan, L., & Zhang, D. D. (2019) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2019.01.016 · Cited by 441 · see citing works
Self-citationThe Impact of Oxidative Stress in Human Pathology: Focus on Gastrointestinal Disorders
Vona, R., Pallotta, L., Cappelletti, M., Severi, C., & Matarrese, P. (2021) · Antioxidants · doi:10.3390/antiox10020201 · Cited by 431 · see citing works
- Authors
- Zhang, D. D., & Hannink, M.
- Affiliations
- University of Missouri (US)
- Venue
- Molecular and Cellular Biology
- Publisher
- Informa UK Limited
- Published
- 2003-11-01
- Volume
- 23
- Issue
- 22
- Pages
- 8137-8151
- ISSN
- 0270-7306 (ISSN-L)
- 1098-5549
- PMC
- PMC262403
- OpenAlex
- W2130029858
- Cited by
- 1,480
- References
- 43
- Citations by year
- 2026: 65 · 2025: 69 · 2024: 68 · 2023: 73 · 2022: 83 · 2021: 87 · 2020: 101 · 2019: 70 · 2018: 79 · 2017: 77 · 2016: 93 · 2015: 72 · 2014: 64 · 2013: 63 · 2012: 62
- FWCI
- 11.15
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Molecular and Cellular Biology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- University of Missouri
- National Institutes of Health
- University of California, San Francisco
- National Institute of General Medical Sciences (GM 59213, R01GM059213)
- National Institute of Environmental Health Sciences (ES 11721, R21ES011721)
- 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, cysteine residues, ubiquitination, protein degradation, proteasome, chemoprevention, sulforaphane, oxidative stress, E3 ubiquitin ligase, protein stabilization, nuclear localization, post-translational modification
- MeSH terms
- Kelch-Like ECH-Associated Protein 1, Animals, Carrier Proteins, Cell Line, Cysteine, Cytoskeletal Proteins, DNA-Binding Proteins, Recombinant Proteins, Sulfoxides, Thiocyanates, Transcription, Genetic, Trans-Activators, Mutagenesis, Anticarcinogenic Agents, Sequence Deletion, Protein Structure, Tertiary, Isothiocyanates, Oxidative Stress, COS Cells, Ubiquitin, NIH 3T3 Cells, Adaptor Proteins, Signal Transducing, NF-E2-Related Factor 2, Mice
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