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. Antioxid. Redox Signal. 13, 1665–1678.
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