The DOI matches its Crossref record; 14 of the 14 references it cites were found in a registry or an index.
Discovery of the Negative Regulator of Nrf2, Keap1: A Historical Overview
Abstract
An antioxidant response element (ARE) or an electrophile responsive element (EpRE) regulate the transcriptional induction of a battery of drug-detoxifying enzymes that are protective against electrophiles. Based on the high similarity of the ARE consensus sequence to an erythroid gene regulatory element NF-E2 binding site, we have found that the transcription factor Nrf2 is indispensable for the ARE-mediated induction of drug-metabolizing enzymes. Recent genome-wide analysis demonstrated that Nrf2 regulates hundreds of genes that are involved in the cytoprotective response against oxidative stress. In-depth analysis of Nrf2 regulatory mechanisms has led us to the discovery of a novel protein, which we have named Keap1. Keap1 suppresses Nrf2 activity by specifically binding to its evolutionarily conserved N-terminal Neh2 regulatory domain. In this review article, we summarize the findings and observations that have lead to the discovery of the Nrf2-Keap1 system. Furthermore, we briefly discuss the function of the Nrf2-Keap1 system under the regulation of the endogenous electrophilic compound 15-deoxy-Δ¹²(,)¹⁴-prostaglandin J₂. We propose that Nrf2-Keap1 plays a significant physiological role in the response to endogenous, environmental, and pharmacological electrophiles.
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Itoh, K., Chiba, T., Takahashi, S., Ishii, T., Igarashi, K., Katoh, Y., Oyake, T., Hayashi, N., Satoh, K., Hatayama, I., et al. (1997) · Biochemical and Biophysical Research Communications · doi:10.1006/bbrc.1997.6943 · Cited by 3,999
Cell Survival Responses to Environmental Stresses Via the Keap1-Nrf2-ARE Pathway
Kensler, T. W., Wakabayashi, N., & Biswal, S. (2007) · Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev.pharmtox.46.120604.141046 · Cited by 3,630
The peroxisome proliferator-activated receptor-γ is a negative regulator of macrophage activation
Ricote, M., Li, A. C., Willson, T. M., Kelly, C. J., & Glass, C. K. (1998) · Nature · doi:10.1038/34178 · Cited by 3,525
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
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
Self-citationNrf2–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 · cited 4×
“The CNC family was named after the similarity of the bZip domain structure in this family of proteins to that of the Drosophila Cap’n’Color (CNC) protein (70).”
InfluentialSelf-citationMoi, 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
Nrf2 is a critical regulator of the innate immune response and survival during experimental sepsis
Thimmulappa, R. K. (2006) · Journal of Clinical Investigation · doi:10.1172/jci25790 · Cited by 1,028 · cited 1×
“Nrf2-KO mice are also susceptible to drug-induced neurodegenerative disorders (5, 97) or inflammation, such as endotoxin shock (105), carrageenin- and elastase-induced lung inflammation (35, 40, 68) and dextran sulfate sodium-induced colitis (52).”
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 · cited 2×
“While the N-terminal subdomain (residues 16–31) contains hydrophobic amino acid residues that can potentially form an amphipathic a -helix (47, 106), the central portion of the domain is rich in hydrophilic residues that may also adopt an a -helical structure (106) (Fig.”
Self-citationStructural 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 · cited 1×
“CTR (C-terminal region) together comprise six-bladed b propeller structure (81) and directly interacts with two Nrf2 Neh2 motifs ( i.e., DLG and ETGE motifs), such that the Keap1 dimer recognizes one molecule of Nrf2 (two-site recognition model) (Figs.”
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Cited by
Kurutas, E. B. (2015) · Nutrition Journal · doi:10.1186/s12937-016-0186-5 · Cited by 2,152
Brigelius-Flohé, R., & Maiorino, M. (2013) · Biochimica et Biophysica Acta (BBA) - General Subjects · doi:10.1016/j.bbagen.2012.11.020 · Cited by 1,904
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
Heme oxygenase-1 mediates BAY 11-7085 induced ferroptosis
Chang, L.-C., Chiang, S.-K., Chen, S.-E., Yu, Y.-L., Chou, R.-H., & Chang, W.-C. (2018) · Cancer Letters · doi:10.1016/j.canlet.2017.12.025 · Cited by 521
Bae, S. H., Sung, S. H., Oh, S. Y., Lim, J. M., Lee, S. K., Park, Y. N., Lee, H. E., Kang, D., & Rhee, S. G. (2013) · Cell Metabolism · doi:10.1016/j.cmet.2012.12.002 · Cited by 492
Metadata
- Authors
- Itoh, K., Mimura, J., & Yamamoto, M.
- Venue
- Antioxidants & Redox Signaling
- Publisher
- SAGE Publications
- Published
- 2010-12
- Volume
- 13
- Issue
- 11
- Pages
- 1665-1678
- ISSN
- 1523-0864 (ISSN-L)
- 1557-7716
- OpenAlex
- W1996521867
- Cited by
- 510
- References
- 14
- FWCI
- 9.57
- Type
- journal article
- Language
- en
- Open access
- closed
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