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Antioxid Redox Signal. 2010 Dec 1;13(11):1665-78. doi: 10.1089/ars.2010.3222. Epub 2010 Jul 13.

Discovery of the negative regulator of Nrf2, Keap1: a historical overview.

Author information

1
Department of Stress Response Science, Hirosaki University Graduate School of Medicine, Japan. itohk@cc.hirosaki-u.ac.jp

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.

PMID:
20446768
DOI:
10.1089/ars.2010.3222
[Indexed for MEDLINE]

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