Signaling by Keap1/Nrf2 mediates the electrophile stress response

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Signaling by Keap1/Nrf2 mediates the electrophile stress response Signaling by Keap1/Nrf2 mediates the electrophile stress response. Normally NF-E2-related factor 2 (Nrf2) is kept inactive and at a low intracellular level by interacting with Keap1 that promotes its proteasomal degradation by ubiquitination. Electrophiles covalently bind to, whereas oxidants oxidize the reactive thiol groups of Keap1, causing Keap1 to release Nrf2. Alternatively, Nrf2 release may follow its phosphorylation by protein kinases. After being released from Keap1, the active Nrf2 accumulates in the cell, translocates into the nucleus, and forms a heterodimer with small Maf proteins to activate genes that contain electrophile response element (EpRE) in their promoter region. These include enzymes, binding proteins, and transporters functioning in detoxication and elimination of xenobiotics, ROS, and endogenous reactive chemicals, as well as some proteins that can repair or eliminate oxidized proteins. Induction of such proteins represents an electrophile stress response that provides protection against a wide range of toxicants. Nrf1, a transcription factor structurally related to Nrf2, also interacts with Keap1 and Maf proteins as well as EpRE and its role is partially overlapping with that of Nrf2. Abbreviations: AR, aldose reductase; CES carboxylesterase; EH1, microsomal epoxide hydrolase; GCL, glutamate–cysteine ligase; GGT, gamma-glutamyl transpeptidase; GPX2, glutathione peroxidase 2; GR, glutathione reductase; GST, glutathione S-transferase; HO-1, heme oxygenase 1; NQO1, NAD(P)H:quinone oxidoreductase; Mrp2, Mrp3, and Mrp4, multidrug resistance protein 2, 3, and 4; SOD1, superoxide dismutase 1; Srx1, sulfiredoxin 1; UGT, UDP-glucuronosyltransferase; Trx, thioredoxin; TrxR, thioredoxin reductase. Source: Mechanisms of Toxicity, Casarett and Doull's Toxicology: The Basic Science of Poisons, 8e Citation: Klaassen CD. Casarett and Doull's Toxicology: The Basic Science of Poisons, 8e; 2012 Available at: https://accesspharmacy.mhmedical.com/DownloadImage.aspx?image=/data/books/958/kla008_fig_03-27.png&sec=53484451&BookID=958&ChapterSecID=53483722&imagename= Accessed: October 30, 2017 Copyright © 2017 McGraw-Hill Education. All rights reserved