title: 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.
authors.affiliation: Department of Stress Response Science, Hirosaki University Graduate School of Medicine, Japan. itohk@cc.hirosaki-u.ac.jp
authors.forename: Ken
authors.initials: K
authors.lastname: Itoh
authors.forename: Junsei
authors.initials: J
authors.lastname: Mimura
authors.forename: Masayuki
authors.initials: M
authors.lastname: Yamamoto
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D001665:Binding Sites; D019610:Cytoprotection; D015870:Gene Expression; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D000072019:Kelch-Like ECH-Associated Protein 1; D050978:Maf Transcription Factors, Small / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress / Q000235:genetics; D011485:Protein Binding; D020218:Response Elements; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D015533:Transcriptional Activation
chemical_list: D000975:Antioxidants; D047908:Intracellular Signaling Peptides and Proteins; C431364:KEAP1 protein, human; D000072019:Kelch-Like ECH-Associated Protein 1; D050978:Maf Transcription Factors, Small; D051267:NF-E2-Related Factor 2; D015534:Trans-Activators; D014157:Transcription Factors