Discovery of the negative regulator of Nrf2, Keap1: a historical overview
- PMID: 20446768
- DOI: 10.1089/ars.2010.3222
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.
Similar articles
-
The Keap1-Nrf2 system as an in vivo sensor for electrophiles.Nitric Oxide. 2011 Aug 1;25(2):153-60. doi: 10.1016/j.niox.2011.02.007. Epub 2011 Mar 6. Nitric Oxide. 2011. PMID: 21385624
-
Cancer chemoprevention mechanisms mediated through the Keap1-Nrf2 pathway.Antioxid Redox Signal. 2010 Dec 1;13(11):1713-48. doi: 10.1089/ars.2010.3221. Epub 2010 Aug 14. Antioxid Redox Signal. 2010. PMID: 20446772 Review.
-
Activation of the Nrf2/ARE pathway via S-alkylation of cysteine 151 in the chemopreventive agent-sensor Keap1 protein by falcarindiol, a conjugated diacetylene compound.Toxicol Appl Pharmacol. 2010 Apr 1;244(1):27-36. doi: 10.1016/j.taap.2009.12.012. Epub 2009 Dec 21. Toxicol Appl Pharmacol. 2010. PMID: 20026152
-
Action of Nrf2 and Keap1 in ARE-mediated NQO1 expression by quercetin.Free Radic Biol Med. 2007 Jun 1;42(11):1690-703. doi: 10.1016/j.freeradbiomed.2007.02.017. Epub 2007 Feb 28. Free Radic Biol Med. 2007. PMID: 17462537
-
Molecular mechanism activating Nrf2-Keap1 pathway in regulation of adaptive response to electrophiles.Free Radic Biol Med. 2004 May 15;36(10):1208-13. doi: 10.1016/j.freeradbiomed.2004.02.075. Free Radic Biol Med. 2004. PMID: 15110385 Review.
Cited by
-
Opportunities and Challenges of Soy Proteins with Different Processing Applications.Antioxidants (Basel). 2024 May 5;13(5):569. doi: 10.3390/antiox13050569. Antioxidants (Basel). 2024. PMID: 38790674 Free PMC article. Review.
-
A High-Fat-Diet-Induced Microbiota Imbalance Correlates with Oxidative Stress and the Inflammatory Response in the Gut of Freshwater Drum (Aplodinotus grunniens).Antioxidants (Basel). 2024 Mar 18;13(3):363. doi: 10.3390/antiox13030363. Antioxidants (Basel). 2024. PMID: 38539896 Free PMC article.
-
Nutrigenomics of Natural Antioxidants in Broilers.Antioxidants (Basel). 2024 Feb 22;13(3):270. doi: 10.3390/antiox13030270. Antioxidants (Basel). 2024. PMID: 38539804 Free PMC article. Review.
-
Crosstalk between MicroRNAs and Oxidative Stress in Coeliac Disease.Inflamm Intest Dis. 2024 Jan 24;9(1):11-21. doi: 10.1159/000536107. eCollection 2024 Jan-Dec. Inflamm Intest Dis. 2024. PMID: 38298886 Free PMC article. Review.
-
Proximity proteomic analysis of the NRF family reveals the Parkinson's disease protein ZNF746/PARIS as a co-complexed repressor of NRF2.Sci Signal. 2023 Dec 12;16(815):eadi9018. doi: 10.1126/scisignal.adi9018. Epub 2023 Dec 12. Sci Signal. 2023. PMID: 38085818
Publication types
MeSH terms
Substances
LinkOut - more resources
Full Text Sources