Cited by 1,480Genomics, phytochemicals, and oxidative stressRedox biology and oxidative stressGlutathione Transferases and Polymorphisms

The DOI matches its Crossref record; 43 of the 43 references it cites were found in a registry or an index.

Distinct Cysteine Residues in Keap1 Are Required for Keap1-Dependent Ubiquitination of Nrf2 and for Stabilization of Nrf2 by Chemopreventive Agents and Oxidative Stress

Open access

Zhang, Donna D., Hannink, Mark·2003·Molecular and Cellular Biology

DOI 10.1128/mcb.23.22.8137-8151.2003PMC PMC262403

Open this paper in CoChat — free account

Abstract

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.

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

Crossref · 10.1128/mcb.23.22.8137-8151.2003

Cites

43 of 43 references verified0 citation errors · 0 not checkable

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?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

1 retracted

SUMO-1 Modification of Mdm2 Prevents Its Self-Ubiquitination and Increases Mdm2 Ability to Ubiquitinate p53
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
Retracted
Keap1 represses nuclear activation of antioxidant responsive elements by Nrf2 through binding to the amino-terminal Neh2 domain
Itoh, K., Wakabayashi, N., Katoh, Y., Ishii, T., Igarashi, K., Engel, J. D., & Yamamoto, M. (1999) · Genes & Development · doi:10.1101/gad.13.1.76 · Cited by 3,634
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
Mechanisms Underlying Ubiquitination
Pickart, C. M. (2001) · Annual Review of Biochemistry · doi:10.1146/annurev.biochem.70.1.503 · Cited by 3,184
Direct evidence that sulfhydryl groups of Keap1 are the sensors regulating induction of phase 2 enzymes that protect against carcinogens and oxidants
Dinkova-Kostova, A. T., Holtzclaw, W. D., Cole, R. N., Itoh, K., Wakabayashi, N., Katoh, Y., Yamamoto, M., & Talalay, P. (2002) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.172398899 · Cited by 1,947
Isolation of NF-E2-related factor 2 (Nrf2), a NF-E2-like basic leucine zipper transcriptional activator that binds to the tandem NF-E2/AP1 repeat of the beta-globin locus control region
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
I NHIBITION OF C ARCINOGENESIS BY D IETARY P OLYPHENOLIC C OMPOUNDS
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
Regulatory Mechanisms Controlling Gene Expression Mediated by the Antioxidant Response Element
Nguyen, T., Sherratt, P. J., & Pickett, C. B. (2003) · The Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev.pharmtox.43.100901.140229 · Cited by 1,232
Untitled work
(2002) · PubMed · Cited by 1,190
Keap1-dependent proteasomal degradation of transcription factor Nrf2 contributes to the negative regulation of antioxidant response element-driven gene expression
McMahon, M., Itoh, K., Yamamoto, M., & Hayes, J. D. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m300931200 · Cited by 1,141

Flagged first, then by citations

Show all 43 references

Research works printed but not linked: 2

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.
Sambrook J. and D. W. Russell. 2001. Molecular cloning: a laboratory manual 3rd ed. Cold Spring Harbor Press Cold Spring Harbor N.Y.

Sorted by citations

Items 601–700 of 1,002

Topical bixin confers NRF2-dependent protection against photodamage and hair graying in mouse skin
Rojo de la Vega, M., Zhang, D. D., & Wondrak, G. T. (2018) · Frontiers in Pharmacology · doi:10.3389/fphar.2018.00287 · Cited by 55
Self-citation
Induction of Nrf2-regulated genes by 3H-1, 2-dithiole-3-thione through the ERK signaling pathway in murine keratinocytes
Manandhar, S., Cho, J.-M., Kim, J., Kensler, T. W., & Kwak, M.-K. (2007) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2007.08.018 · Cited by 58
Inhibition of hypoxia inducible factor by phenethyl isothiocyanate
Wang, X., Cavell, B. E., Alwi, S. S. S., & Packham, G. (2009) · Biochemical Pharmacology · doi:10.1016/j.bcp.2009.04.010 · Cited by 59
Sulforaphane Induces Antioxidative and Antiproliferative Responses by Generating Reactive Oxygen Species in Human Bronchial Epithelial BEAS-2B Cells
Lee, Y., & Lee, S.-H. (2011) · Journal of Korean Medical Science · doi:10.3346/jkms.2011.26.11.1474 · Cited by 58
Deletion of Nrf2 leads to hepatic insulin resistance via the activation of NF-κB in mice fed a high-fat diet
Liu, Z., Dou, W., Ni, Z., Wen, Q., Zhang, R., Qin, M., Wang, X., Tang, H., Cao, Y., Wang, J., et al. (2016) · Molecular Medicine Reports · doi:10.3892/mmr.2016.5393 · Cited by 59
Exploring the Use of Dimethyl Fumarate as Microglia Modulator for Neurodegenerative Diseases Treatment
Rosito, M., Testi, C., Parisi, G., Cortese, B., Baiocco, P., & Angelantonio, S. D. (2020) · Antioxidants · doi:10.3390/antiox9080700 · Cited by 61
Geldanamycin-Derived HSP90 Inhibitors Are Synthetic Lethal with NRF2
Baird, L., Suzuki, T., Takahashi, Y., Hishinuma, E., Saigusa, D., & Yamamoto, M. P. (2020) · Molecular and Cellular Biology · doi:10.1128/mcb.00377-20 · Cited by 57
Cell Cycle Regulation by Oncogenic Tyrosine Kinases in Myeloid Neoplasias: From Molecular Redox Mechanisms to Health Implications
Rodrigues, M. S., Reddy, M. M., & Sattler, M. (2008) · Antioxidants and Redox Signaling · doi:10.1089/ars.2008.2071 · Cited by 58
Function of specialized regulatory proteins and signaling pathways in exercise-induced muscle mitochondrial biogenesis
Erlich, A. T., Tryon, L. D., Crilly, M. J., Memme, J. M., Moosavi, Z. S. M., Oliveira, A. N., Beyfuss, K. A., & Hood, D. A. (2016) · Integrative Medicine Research · doi:10.1016/j.imr.2016.05.003 · Cited by 59
Rutin protects against H 2 O 2 -triggered impaired relaxation of placental arterioles and induces Nrf2-mediated adaptation in Human Umbilical Vein Endothelial Cells exposed to oxidative stress
Sthijns, M. M. J. P. E., Schiffers, P. M. H., Janssen, G. M. J., Lemmens, K. J. A., Ides, B., Vangrieken, P., Bouwman, F. G., Mariman, E. C. M., Pader, I., Arnér, E. S. J., et al. (2017) · Biochimica et Biophysica Acta (BBA) - General Subjects · doi:10.1016/j.bbagen.2017.03.004 · Cited by 59
CRL3s: The BTB-CUL3-RING E3 Ubiquitin Ligases
Wang, P., Song, J., & Ye, D. (2020) · Advances in experimental medicine and biology · doi:10.1007/978-981-15-1025-0_13 · Cited by 53
Identification of the NRF2 transcriptional network as a therapeutic target for trigeminal neuropathic pain
Vasavda, C., Xu, R., Liew, J., Kothari, R., Dhindsa, R. S., Semenza, E. R., Paul, B. D., Green, D. P., Sabbagh, M. F., Shin, J. Y., et al. (2022) · Science Advances · doi:10.1126/sciadv.abo5633 · Cited by 59
Effect of Coffee Combining Green Coffee Bean Constituents with Typical Roasting Products on the Nrf2/ARE Pathway in Vitro and in Vivo
Volz, N., Boettler, U., Winkler, S., Teller, N., Schwarz, C. C., Bakuradze, T., Eisenbrand, G., Haupt, L. M., Griffiths, L. R., Stiebitz, H., et al. (2012) · Journal of Agricultural and Food Chemistry · doi:10.1021/jf302258u · Cited by 56
Keap1–Nrf2 signalling in pancreatic cancer
Hayes, A. J., Skouras, C., Haugk, B., & Charnley, R. (2015) · The International Journal of Biochemistry & Cell Biology · doi:10.1016/j.biocel.2015.06.017 · Cited by 56
Dynamics of Nrf2 and Keap1 in ARE-Mediated NQO1 Expression by Wasabi 6-(Methylsulfinyl)hexyl Isothiocyanate
Hou, D., Korenori, Y., Tanigawa, S., Yamada‐Kato, T., Nagai, M., He, X., & He, J. (2011) · Journal of Agricultural and Food Chemistry · doi:10.1021/jf2032439 · Cited by 57
Induction of Heme Oxygenase I (HMOX1) by HPP-4382: A Novel Modulator of Bach1 Activity
Attucks, O. C., Jasmer, K. J., Hannink, M., Kassis, J. N., Zhong, Z., Gupta, S., Victory, S. F., Güzel, M., Rao, P. D., Andrews, R., et al. (2014) · PLoS ONE · doi:10.1371/journal.pone.0101044 · Cited by 55
Self-citation
Design and Synthesis of Irreversible Analogues of Bardoxolone Methyl for the Identification of Pharmacologically Relevant Targets and Interaction Sites
Wong, M. H. L., Bryan, H. K., Copple, I. M., Jenkins, R. E., Chiu, P. H., Bibby, J., Berry, N. G., Kitteringham, N. R., Goldring, C. E., O’Neill, P. M., et al. (2016) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.5b01292 · Cited by 56
Cytochrome P450 2A5 Constitutive Expression and Induction by Heavy Metals Is Dependent on Redox-Sensitive Transcription Factor Nrf2 in Liver
Lämsä, V., Levonen, A., Leinonen, H. M., Ylä‐Herttuala, S., Yamamoto, M. P., & Hakkola, J. (2010) · Chemical Research in Toxicology · doi:10.1021/tx100084c · Cited by 57
Select Heterozygous Keap1 Mutations Have a Dominant-Negative Effect on Wild-Type Keap1 In Vivo
Suzuki, T., Maher, J. M., & Yamamoto, M. P. (2010) · Cancer Research · doi:10.1158/0008-5472.can-10-2939 · Cited by 55
The functional interactome of GSTP: A regulatory biomolecular network at the interface with the Nrf2 adaption response to oxidative stress
Bartolini, D., & Galli, F. (2016) · Journal of Chromatography B · doi:10.1016/j.jchromb.2016.02.002 · Cited by 55
ALS-FTLD associated mutations of SQSTM1 impact on Keap1-Nrf2 signalling
Goode, A., Rea, S. L., Sultana, M., Shaw, B., Searle, M. S., & Layfield, R. (2016) · Molecular and Cellular Neuroscience · doi:10.1016/j.mcn.2016.08.004 · Cited by 56
An in vitro inflammation model to study the Nrf2 and NF-κB crosstalk in presence of ferulic acid as modulator
Lampiasi, N., & Montana, G. (2017) · Immunobiology · doi:10.1016/j.imbio.2017.10.046 · Cited by 56
Nrf2 as a potential target for Parkinson’s disease therapy
Niu, Y., Zhang, J., & Dong, M. (2021) · Journal of Molecular Medicine · doi:10.1007/s00109-021-02071-5 · Cited by 54
Redox‐sensitive regulation of gene expression in human primary macrophages exposed to inorganic arsenic
Bourdonnay, E., Morzadec, C., Fardel, O., & Vernhet, L. (2009) · Journal of Cellular Biochemistry · doi:10.1002/jcb.22155 · Cited by 58
Electrophilic Chemicals but not UV Irradiation or Reactive Oxygen Species Activate Nrf2 in Keratinocytes In Vitro and In Vivo
Durchdewald, M., Beyer, T. A., Johnson, D. A., Johnson, J. A., Werner, S., & Keller, U. A. D. (2006) · Journal of Investigative Dermatology · doi:10.1038/sj.jid.5700585 · Cited by 53
Role of Reductive versus Oxidative Stress in Tumor Progression and Anticancer Drug Resistance
Chun, K., Kim, D., & Surh, Y. (2021) · Cells · doi:10.3390/cells10040758 · Cited by 56
Ellagic acid activates the Keap1-Nrf2-ARE signaling pathway in improving Parkinson’s disease: A review
Wang, Q., Botchway, B. O. A., Zhang, Y., & Liu, X. (2022) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2022.113848 · Cited by 52
Enhanced Nrf2-dependent induction of glutathione in mouse embryonic fibroblasts by isoselenocyanate analog of sulforaphane
Emmert, S. W., Desai, D. H., Amin, S., & Richie, J. P. (2010) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2010.01.044 · Cited by 54
The relevant targets of anti-oxidative stress: a review
Qi, J., & Dong, F.-X. (2021) · Journal of drug targeting · doi:10.1080/1061186x.2020.1870987 · Cited by 54
The Nrf2-Keap1 pathway is activated by steroid hormone signaling to govern neuronal remodeling
Chew, L. Y., Zhang, H., He, J., & Yu, F. (2021) · Cell Reports · doi:10.1016/j.celrep.2021.109466 · Cited by 53
Selective disruption of NRF2-KEAP1 interaction leads to NASH resolution and reduction of liver fibrosis in mice
Seedorf, K., Weber, C., Vinson, C., Berger, S., Vuillard, L.-M., Kiss, A., Creusot, S., Broux, O., Géant, A., Ilic, C., et al. (2022) · JHEP Reports · doi:10.1016/j.jhepr.2022.100651 · Cited by 54
Genetic variation in the Nrf2 promoter associates with defective spermatogenesis in humans
Yu, B., Lin, H., Yang, L., Chen, K., Luo, H., Liu, J., Gao, X., Xia, X., & Huang, Z. (2012) · Journal of Molecular Medicine · doi:10.1007/s00109-012-0914-z · Cited by 53
ERRβ: A potent inhibitor of Nrf2 transcriptional activity
Zhou, W., Lo, S., Liu, J.-H., Hannink, M., & Lubahn, D. B. (2007) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2007.08.011 · Cited by 53
Self-citation
Moringa oleifera Lam: Targeting Chemoprevention
Karim, N. A. A., & Ibrahim, M. D. (2016) · PubMed · doi:10.14456/apjcp.2016.155 · Cited by 54
Phenethyl Isothiocyanate, a Dual Activator of Transcription Factors NRF2 and HSF1
Naidu, S. D., Suzuki, T., Yamamoto, M. P., Fahey, J. W., & Dinkova‐Kostova, A. T. (2018) · Molecular Nutrition & Food Research · doi:10.1002/mnfr.201700908 · Cited by 53
A Role for Nrf2 Expression in Defining the Aging of Hippocampal Neural Stem Cells
Ray, S., Corenblum, M. J., Anandhan, A., Reed, A., Ortiz, F., Zhang, D. D., Barnes, C. A., & Madhavan, L. (2018) · Cell Transplantation · doi:10.1177/0963689718774030 · Cited by 54
Self-citation
Antioxidant and antihypertensive responses to oral nitrite involves activation of the Nrf2 pathway
Amaral, J. H., Rizzi, É., Alves-Lopes, R., Pinheiro, L. C., Tostes, R. C., & Tanus-Santos, J. E. (2019) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2019.06.028 · Cited by 54
Recent progress in the development of small molecule Nrf2 activators: a patent review (2017-present)
Zhou, H.-S., Wang, Y., You, Q., & Jiang, Z. (2020) · Expert Opinion on Therapeutic Patents · doi:10.1080/13543776.2020.1715365 · Cited by 53
p62/SQSTM1, a Central but Unexploited Target: Advances in Its Physiological/Pathogenic Functions and Small Molecular Modulators
Chen, Y., Li, Q., Li, Q., Xing, S., Liu, Y., Liu, Y., Chen, Y., Liu, W., Feng, F., & Sun, H. (2020) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.9b02038 · Cited by 56
Nrf2 is activated by disruption of mitochondrial thiol homeostasis but not by enhanced mitochondrial superoxide production
Cvetko, F., Caldwell, S. T., Higgins, M., Suzuki, T., Yamamoto, M. P., Prag, H. A., Hartley, R. C., Dinkova‐Kostova, A. T., & Murphy, M. P. (2020) · Journal of Biological Chemistry · doi:10.1074/jbc.ra120.016551 · Cited by 54
Rosmarinic acid prevents refractory bacterial pneumonia through regulating Keap1/Nrf2-mediated autophagic pathway and mitochondrial oxidative stress
Zhang, W. K., Cheng, C., Sha, Z., Chen, C., Yu, C., Lv, N., Ji, P., Wu, X., Ma, T., Cheng, H., et al. (2021) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2021.03.038 · Cited by 53
Nrf2, the Major Regulator of the Cellular Oxidative Stress Response, is Partially Disordered
Karunatilleke, N. C., Fast, C. S., Ngo, V., Brickenden, A. M., Duennwald, M. L., Konermann, L., & Choy, W. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22147434 · Cited by 52
Physical-Exercise-Induced Antioxidant Effects on the Brain and Skeletal Muscle
Souza, J., da Silva, R. A., Scheffer, D. D. L., dos Santos, R. P., Solano, A. F., Barros, L., Budde, H., Trostchansky, A., & Latini, A. (2022) · Antioxidants · doi:10.3390/antiox11050826 · Cited by 54
Physiological cyclic strain promotes endothelial cell survival via the induction of heme oxygenase-1
Liu, X., Peyton, K. J., & Durante, W. (2013) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.00872.2012 · Cited by 52
Mechanisms Behind Resistance to PI3K Inhibitor Treatment Induced by the PIM Kinase
Song, J. H., Singh, N., Luevano, L. A., Padi, S. K. R., Okumura, K., Olive, V., Black, S. M., Warfel, N. A., Goodrich, D. W., & Kraft, A. S. (2018) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-18-0374 · Cited by 52
The protective effect of natural medicines against excessive inflammation and oxidative stress in acute lung injury by regulating the Nrf2 signaling pathway
Luan, R., Ding, D., & Yang, J. (2022) · Frontiers in Pharmacology · doi:10.3389/fphar.2022.1039022 · Cited by 53
Baicalein modulates Nrf2/Keap1 system in both Keap1-dependent and Keap1-independent mechanisms
Qin, S., Deng, F., Wu, W., Jiang, L., Yamashiro, T., Yano, S., & Hou, D. (2014) · Archives of Biochemistry and Biophysics · doi:10.1016/j.abb.2014.03.011 · Cited by 51
Hypochlorous acid-induced heme oxygenase-1 gene expression promotes human endothelial cell survival
Wei, Y., Liu, X., Peyton, K. J., Wang, H., Johnson, F. K., Johnson, R. A., & Durante, W. (2009) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00536.2008 · Cited by 51
Keap1–Nrf2 pathway: A promising target towards lung cancer prevention and therapeutics
Tong, Y., Zhang, B., Fan, Y., & Lin, N. (2015) · Chronic Diseases and Translational Medicine · doi:10.1016/j.cdtm.2015.09.002 · Cited by 51
Sulforaphane inhibits platelet-derived growth factor-induced vascular smooth muscle cell proliferation by targeting mTOR/p70S6kinase signaling independent of Nrf2 activation
Shawky, N. M., & Segar, L. (2017) · Pharmacological Research · doi:10.1016/j.phrs.2017.02.010 · Cited by 51
Effects of photoperiod on growth, lipid metabolism and oxidative stress of juvenile gibel carp (Carassius auratus)
Wei, H., Cai, W., Liu, H., Han, D. H., Zhu, X., Yang, Y., Jin, J., & Xie, S.-Q. (2019) · Journal of Photochemistry and Photobiology B Biology · doi:10.1016/j.jphotobiol.2019.111552 · Cited by 52
Effect of Hepatitis Viruses on the Nrf2/Keap1-Signaling Pathway and Its Impact on Viral Replication and Pathogenesis
Bender, D., & Hildt, E. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20184659 · Cited by 56
Sulforaphane-Induced Klf9/Prdx6 Axis Acts as a Molecular Switch to Control Redox Signaling and Determines Fate of Cells
Chhunchha, B., Kubo, E., & Singh, D. P. (2019) · Cells · doi:10.3390/cells8101159 · Cited by 51
Histone deacetylase 3 inhibition alleviates type 2 diabetes mellitus-induced endothelial dysfunction via Nrf2
Huang, S., Chen, G., Sun, J. M., Chen, Y., Wang, N., Dong, Y., Shen, E., Hu, Z., Gong, W., Jin, L., et al. (2021) · Cell Communication and Signaling · doi:10.1186/s12964-020-00681-z · Cited by 50
Keap1-independent Nrf2 regulation: A novel therapeutic target for treating kidney disease
Zhang, J., Zhang, M., Tatar, M., & Gong, R. (2025) · Redox Biology · doi:10.1016/j.redox.2025.103593 · Cited by 58
Role of the Nrf2-ARE pathway in acrylamide neurotoxicity
Zhang, L., Gavin, T., Barber, D. S., & LoPachin, R. M. (2011) · Toxicology Letters · doi:10.1016/j.toxlet.2011.04.011 · Cited by 50
Phytochemicals and botanical extracts regulate NF-κB and Nrf2/ARE reporter activities in DI TNC1 astrocytes
Ajit, D., Simonyi, Á., Li, R., Chen, Z., Hannink, M., Fritsche, K. L., Mossine, V. V., Smith, R. E., Dobbs, T. K., Luo, R., et al. (2016) · Neurochemistry International · doi:10.1016/j.neuint.2016.05.004 · Cited by 50
Self-citation
Targeting glutathione S-transferase P and its interactome with selenium compounds in cancer therapy
Bartolini, D., Torquato, P., Piroddi, M., & Galli, F. (2018) · Biochimica et Biophysica Acta (BBA) - General Subjects · doi:10.1016/j.bbagen.2018.09.023 · Cited by 51
HDAC5 catalytic activity suppresses cardiomyocyte oxidative stress and NRF2 target gene expression
Hu, T., Schreiter, F. C., Bagchi, R. A., Tatman, P. D., Hannink, M., & McKinsey, T. A. (2019) · Journal of Biological Chemistry · doi:10.1074/jbc.ra118.007006 · Cited by 50
Self-citation
CDDO-imidazolide Targets Multiple Amino Acid Residues on the Nrf2 Adaptor, Keap1
Meng, X., Waddington, J. C., Tailor, A., Lister, A., Hamlett, J., Berry, N. G., Park, B. K., & Sporn, M. B. (2020) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.0c01088 · Cited by 50
Structural analysis of the complex of Keap1 with a prothymosin α peptide
Padmanabhan, B., Nakamura, Y., & Yokoyama, S. (2008) · Acta Crystallographica Section F Structural Biology and Crystallization Communications · doi:10.1107/s1744309108004995 · Cited by 50
Redox balance and autophagy regulation in cancer progression and their therapeutic perspective
Khan, S. U., Fatima, K., Aisha, S., Hamza, B., & Malik, F. A. (2022) · Medical Oncology · doi:10.1007/s12032-022-01871-0 · Cited by 50
The role of Nrf2 in periodontal disease by regulating lipid peroxidation, inflammation and apoptosis
Ma, F., Luo, S., Lu, C., Jiang, X., Chen, K., Deng, J., Ma, S., & Li, Z. (2022) · Frontiers in Endocrinology · doi:10.3389/fendo.2022.963451 · Cited by 51
Post-translational modifications of Keap1: the state of the art
Song, Y., Qu, Y., Mao, C., Zhang, R., Jiang, D., & Sun, X. (2024) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2023.1332049 · Cited by 52
The cap’n’collar transcription factor Nrf2 mediates both intrinsic resistance to environmental stressors and an adaptive response elicited by chemopreventive agents that determines susceptibility to electrophilic xenobiotics
Higgins, L. G., & Hayes, J. D. (2010) · Chemico-Biological Interactions · doi:10.1016/j.cbi.2010.09.025 · Cited by 49
New Insights into Neuroblastoma Cisplatin Resistance: A Comparative Proteomic and Meta-Mining Investigation
D’Aguanno, S., D’Alessandro, A., Pieroni, L., Roveri, A., Zaccarin, M., Marzano, V., Canio, M. D., Bernardini, S., Federici, G., & Urbani, A. (2010) · Journal of Proteome Research · doi:10.1021/pr100457n · Cited by 49
Phosphorylation and Dephosphorylation of Tyrosine 141 Regulate Stability and Degradation of INrf2
Jain, A. K., Mahajan, S., & Jaiswal, A. K. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m709854200 · Cited by 49
Retracted
Quinone Methides and their Prodrugs: A Subtle Equilibrium Between Cancer Promotion, Prevention, and Cure
Dufrasne, F., Gelbcke, M., Nève, J., Robert Kiss, A., & Kraus, J. (2011) · Current Medicinal Chemistry · doi:10.2174/092986711796957301 · Cited by 49
Role of Catechin Quinones in the Induction of EpRE-Mediated Gene Expression
Muzolf-Panek, M., Gliszczyńska‐Świgło, A., de Haan, L., Aarts, J. M. M. J. G., Szymusiak, H., Vervoort, J. J. M., Tyrakowska, B., & Rietjens, I. M. C. M. (2008) · Chemical Research in Toxicology · doi:10.1021/tx8001498 · Cited by 49
Nrf2 Activation Involves an Oxidative-Stress Independent Pathway in Tetrafluoroethylcysteine-Induced Cytotoxicity
Ho, H. K., White, C. C., Fernández, C., Fausto, N., Kavanagh, T. J., Nelson, S. D., & Bruschi, S. A. (2005) · Toxicological Sciences · doi:10.1093/toxsci/kfi205 · Cited by 49
HIV-1 decreases Nrf2/ARE activity and phagocytic function in alveolar macrophages
Staitieh, B. S., Ding, L., Neveu, W. A., Spearman, P. W., Guidot, D. M., & Fan, X. (2017) · Journal of Leukocyte Biology · doi:10.1189/jlb.4a0616-282rr · Cited by 49
Nitric Oxide Engages an Anti-inflammatory Feedback Loop Mediated by Peroxiredoxin 5 in Phagocytes
Graham, D. B., Jasso, G. J., Mok, A., Goel, G., Ng, A., Kolde, R., Varma, M., Doench, J. G., Root, D. E., Clish, C. B., et al. (2018) · Cell Reports · doi:10.1016/j.celrep.2018.06.081 · Cited by 51
Post-translational modifications in MeHg-induced neurotoxicity
Ke, T., Gonçalves, F. M., Gonçalves, C. L., dos Santos, A. A., da Rocha, J. B. T., Farina, M., Skalny, A. V., Tsatsakis, A. M., Bowman, A. B., & Aschner, M. (2018) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2018.10.024 · Cited by 47
Design, Synthesis, and Structure–Activity Relationships of Indoline-Based Kelch-like ECH-Associated Protein 1-Nuclear Factor (Erythroid-Derived 2)-Like 2 (Keap1-Nrf2) Protein–Protein Interaction Inhibitors
Zhou, H.-S., Hu, L.-B., Zhang, H., Shan, W.-X., Wang, Y., Li, X., Liu, T., Zhao, J., You, Q., & Jiang, Z. (2020) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.0c01116 · Cited by 49
Ethyl pyruvate-mediated Nrf2 activation and hemeoxygenase 1 induction in astrocytes confer protective effects via autocrine and paracrine mechanisms
Shin, J., Kim, S.-W., Jin, Y., Kim, I., & Lee, J.-K. (2012) · Neurochemistry International · doi:10.1016/j.neuint.2012.04.005 · Cited by 48
The Roles of Reactive Oxygen Species and Autophagy in Mediating the Tolerance of Tumor Cells to Cycling Hypoxia
Koritzinsky, M., & Wouters, B. G. (2013) · Seminars in Radiation Oncology · doi:10.1016/j.semradonc.2013.05.006 · Cited by 50
The redox-sensing gene Nrf2 affects intestinal homeostasis, insecticide resistance, and Zika virus susceptibility in the mosquito Aedes aegypti
Bottino-Rojas, V., Talyuli, O. A. C., Carrara, L., Martins, A. J., James, A. A., de Oliveira, P. L., & Paiva‐Silva, G. O. (2018) · Journal of Biological Chemistry · doi:10.1074/jbc.ra117.001589 · Cited by 46
NRF2 activation by reversible KEAP1 binding induces the antioxidant response in primary neurons and astrocytes of a Huntington's disease mouse model
Moretti, D., Tambone, S., Cerretani, M., Fezzardi, P., Missineo, A., Toledo‐Sherman, L., Muñoz-Sanjuán, I., Harper, S., Dominquez, C., Pacifici, R. E., et al. (2020) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2020.10.022 · Cited by 53
Inhibition of the NRF2/KEAP1 Axis: A Promising Therapeutic Strategy to Alter Redox Balance of Cancer Cells
Panieri, E., & Saso, L. (2021) · Antioxidants and Redox Signaling · doi:10.1089/ars.2020.8146 · Cited by 46
Activation of the Nrf2-ARE Pathway in Hepatocytes Protects Against Steatosis in Nutritionally Induced Non-alcoholic Steatohepatitis in Mice
Lee, L., Köhler, U. A., Zhang, L. R., Roenneburg, D. A., Werner, S., Johnson, J. A., & Foley, D. P. (2014) · Toxicological Sciences · doi:10.1093/toxsci/kfu184 · Cited by 47
Redox Molecular Machines Involved in Tumor Progression
Parri, M., & Chiarugi, P. (2012) · Antioxidants and Redox Signaling · doi:10.1089/ars.2012.5040 · Cited by 47
Microarray and pathway analysis highlight Nrf2/ARE-mediated expression profiling by polyphenolic myricetin.
Qin, S., Chen, J.-H., Tanigawa, S., & Hou, D.-X. (2013) · Molecular Nutrition & Food Research · doi:10.1002/mnfr.201200563 · Cited by 45
Curcumin Blocks Interleukin-1 (IL-1) Signaling by Inhibiting the Recruitment of the IL-1 Receptor–Associated Kinase IRAK in Murine Thymoma EL-4 Cells
Jurrmann, N., Brigelius‐Flohé, R., & Böl, G. (2005) · Journal of Nutrition · doi:10.1093/jn/135.8.1859 · Cited by 47
Bailcalin Protects against Diabetic Cardiomyopathy through Keap1/Nrf2/AMPK-Mediated Antioxidative and Lipid-Lowering Effects
Li, R., Liu, Y., Shan, Y., Gao, L., Wang, F., & Qiu, C. (2019) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2019/3206542 · Cited by 47
Regulator of G protein signaling 12 enhances osteoclastogenesis by suppressing Nrf2-dependent antioxidant proteins to promote the generation of reactive oxygen species
Ng, A. Y. H., Li, Z., Jones, M. M., Yang, S., Li, C., Fu, C., Tu, C., Oursler, M. J., Qu, J., & Yang, S. (2019) · eLife · doi:10.7554/elife.42951 · Cited by 47
JunB and JunD Regulate Human Heme Oxygenase-1 Gene Expression in Renal Epithelial Cells
Hock, T., Liby, K. T., Wright, M. M., McConnell, S. C., Schorpp‐Kistner, M., Ryan, T. M., & Agarwal, A. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m608456200 · Cited by 47
Regulation of the cadmium stress response through SCF-like ubiquitin ligases: comparison between Saccharomyces cerevisiae, Schizosaccharomyces pombe and mammalian cells
Baudouin‐Cornu, P., & Labarre, J. (2006) · Biochimie · doi:10.1016/j.biochi.2006.03.001 · Cited by 46
PHLPP2 down regulation influences nuclear Nrf2 stability via Akt-1/Gsk3β/Fyn kinase axis in acetaminophen induced oxidative renal toxicity: Protection accorded by morin
Mathur, A., Rizvi, F., & Kakkar, P. (2016) · Food and Chemical Toxicology · doi:10.1016/j.fct.2016.01.001 · Cited by 46
Zinc-binding triggers a conformational-switch in the cullin-3 substrate adaptor protein KEAP1 that controls transcription factor NRF2
McMahon, M. J., Swift, S., & Hayes, J. D. (2018) · Toxicology and Applied Pharmacology · doi:10.1016/j.taap.2018.09.033 · Cited by 46
Redox Homeostasis and Natural Dietary Compounds: Focusing on Antioxidants of Rice (Oryza sativa L.)
Rungratanawanich, W., Memo, M., & Uberti, D. L. (2018) · Nutrients · doi:10.3390/nu10111605 · Cited by 50
Rescue of TCA Cycle Dysfunction for Cancer Therapy
Marquez, J. C., Flores, J., Kim, A. H., Nyamaa, B., Nguyen, A. T. T., Park, N., & Han, J. (2019) · Journal of Clinical Medicine · doi:10.3390/jcm8122161 · Cited by 47
Significance of NRF2 in physiological and pathological conditions an comprehensive review
Kryszczuk, M., & Kowalczuk, O. (2022) · Archives of Biochemistry and Biophysics · doi:10.1016/j.abb.2022.109417 · Cited by 44
Curcumin analog 1, 5-bis (2-trifluoromethylphenyl)-1, 4-pentadien-3-one exhibits enhanced ability on Nrf2 activation and protection against acrolein-induced ARPE-19 cell toxicity
Li, Y., Zou, X., Cao, K. J., Xu, J., Yue, T., Dai, F., Zhou, B., Lu, W., Feng, Z., & Liu, J. (2013) · Toxicology and Applied Pharmacology · doi:10.1016/j.taap.2013.07.029 · Cited by 45
The role of c-Jun phosphorylation in EpRE activation of phase II genes
Levy, S., Jaiswal, A. K., & Forman, H. J. (2009) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2009.07.036 · Cited by 45
Artemisitene activates the Nrf2‐dependent antioxidant response and protects against bleomycin‐induced lung injury
Chen, W., Li, S., Li, J., Zhou, W., Wu, S., Xu, S., Cui, K., Zhang, D. D., & Liu, B. (2016) · The FASEB Journal · doi:10.1096/fj.201500109r · Cited by 45
Self-citation
Enhanced p62-NRF2 Feedback Loop due to Impaired Autophagic Flux Contributes to Arsenic-Induced Malignant Transformation of Human Keratinocytes
Wu, X., Sun, R. B., Wang, H., Yang, B., Wang, F., Xu, H., Chen, S., Zhao, R., Pi, J., & Xu, Y. (2019) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2019/1038932 · Cited by 44
NRF2 as a therapeutic opportunity to impact in the molecular roadmap of ALS
Jiménez-Villegas, J., Ferraiuolo, L., Mead, R. J., Shaw, P. J., Cuadrado, A., & Rojo, A. I. (2021) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2021.07.022 · Cited by 44
Newly constructed stable reporter cell lines for mechanistic studies on electrophile-responsive element-mediated gene expression reveal a role for flavonoid planarity
Boerboom, A.-M. J. F., Vermeulen, M., van der Woude, H., Bremer, B. I., Lee-Hilz, Y. Y., Kampman, E., van BLADEREN, P. J., Rietjens, I. M. C. M., & Aarts, J. M. M. J. G. (2006) · Biochemical Pharmacology · doi:10.1016/j.bcp.2006.04.002 · Cited by 45
Lignans from Eucommia ulmoides Oliver leaves exhibit neuroprotective effects via activation of the PI3K/Akt/GSK-3β/Nrf2 signaling pathways in H2O2-treated PC-12 cells
Han, R., Yu, Y., Zhao, K., Wei, J., Hui, Y., & Gao, J. (2022) · Phytomedicine · doi:10.1016/j.phymed.2022.154124 · Cited by 47
Epigenetic Therapeutics Targeting NRF2/KEAP1 Signaling in Cancer Oxidative Stress
Zhang, S., Duan, S., Xie, Z., Bao, W., Xu, B., Yang, W., & Zhou, L. (2022) · Frontiers in Pharmacology · doi:10.3389/fphar.2022.924817 · Cited by 50

Authors: Zhang, D. D., & Hannink, M.
Affiliations: University of Missouri (US)
ORCID: Zhang, Donna D.
Hannink, Mark
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
DOI: 10.1128/mcb.23.22.8137-8151.2003
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
Licence: journals.asm.org/non-commercial-tdm-license (tdm)
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

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

Distinct Cysteine Residues in Keap1 Are Required for Keap1-Dependent Ubiquitination of Nrf2 and for Stabilization of Nrf2 by Chemopreventive Agents and Oxidative Stress

Abstract

Overview

Integrity signals

Verification

Claims the paper makes

Claims other papers make about this one

Self-check

Citations

Cites

Cited by

Related

Metadata

Record

About these checks