ANRV298-PA47-03 ARI 7 December 2006 15:6Cell Survival Responses toEnvironmental Stresses Viathe Keap1-Nrf2-AREPathwayThomas W. Kensler, Nobunao Wakabayashi,and Shyam BiswalDepartment of Environmental Health Sciences, Johns Hopkins Bloomberg School ofPublic Health, Baltimore, Maryland 21205; email: [email protected],[email protected], [email protected]. Rev. Pharmacol. Toxicol. 2007. 47:89–116First published online as a Review in Advance onAugust 29, 2006The Annual Review of Pharmacology and Toxicology isonline at http://pharmtox.annualreviews.orgThis article’s doi:10.1146/annurev.pharmtox.46.120604.141046Copyrightc 2007 by Annual Reviews.All rights reserved0362-1642/07/0210-0089$20.00Key Wordsantioxidant response element, oxidative stress, cytoprotection, geneexpression, knockout miceAbstractKeap1-Nrf2-ARE signaling plays a significant role in protecting cellsfrom endogenous and exogenous stresses. The development of Nrf2knockout mice has provided key insights into the toxicological im-portance of this pathway. These mice are more sensitive to the hep-atic, pulmonary, ovarian, and neurotoxic consequences of acute ex-posures to environmental agents and drugs, inflammatory stresses, aswell as chronic exposures to cigarette smoke and other carcinogens.Under quiescent conditions, the transcription factor Nrf2 interactswith the actin-anchored protein Keap1, largely localized in the cy-toplasm. This quenching interaction maintains low basal expressionof Nrf2-regulated genes. However, upon recognition of chemicalsignals imparted by oxidative and electrophilic molecules, Nrf2 isreleased from Keap1, escapes proteasomal degradation, translocatesto the nucleus, and transactivates the expression of several dozen cy-toprotective genes that enhance cell survival. This review highlightsthe key elements in this adaptive response to protection against acuteand chronic cell injury provoked by environmental stresses.89Annu. Rev. Pharmacol. Toxicol. 2007.47:89-116. Downloaded from arjournals.annualreviews.orgby University of North Carolina - Chapel Hill on 03/04/07. For personal use only.ANRV298-PA47-03 ARI 7 December 2006 15:6ARE: antioxidant responseelementKEAP1: Kelch ECHAssociating Protein 1NRF2: nuclear factorerythroid 2-related factor 2INTRODUCTIONThe relentless stresses imposed by electrophiles and oxidants exacerbate many chronicdiseases. For example, oxidative stress contributes to aging and age-related diseasessuch as cancer, cardiovascular disease, chronic inflammation, and neurodegenerativediseases. Levels of oxidized proteins, phospholipids, and DNA increase in these pro-cesses. In addition, DNA-damaging electrophiles are often carcinogens. Cells havedeveloped adaptive, dynamic programs to counteract environmental stresses imposedby intrinsic and extrinsic oxidants and electrophiles. These systems may be dividedinto four categories: (a) oxidations and reductions, which introduce or expose func-tional groups onto largely hydrophobic organic molecules and are often catalyzed bycytochrome P450 enzymes; (b) nucleophilic trapping processes that add glutathioneor other cellular nucleophiles to electrophilic xenobiotics, such as those catalyzedby glutathione S-transferases (GSTs) and conjugations of electrophilic adenosine-containing cofactors with nucleophilic xenobiotics (e.g., UDP-glucuronosyl trans-ferases), which often facilitate their excretion, as well as enzymes such as superoxidedismutases, glutathione peroxidase, and catalase, which inactivate reactive oxygenspecies; (c) efflux transporters that export toxic metabolites; and (d) thiol-containingmolecules, such as glutathione and thioredoxin, which function to maintain reduc-ing conditions within the cell. Often the outcome of the encounter of a cell with apotentially toxic agent is largely determined by the balance between the activitiesof the enzymes that activate substrates to reactive intermediates, and the activitiesof the enzymes that detoxify these reactive species. Normally, the conjugating andrelated enzymes are not expressed at their maximal capacity but are highly inducibleby transcriptional activation, and they exert versatile, long-acting, and often catalyticprotection against electrophile and oxidant damage.As depicted in Figure 1, induction of this protective response requires at leastthree essential components: (a) antioxidant response elements (AREs) (1), upstreamregulatory sequences present on each gene in either single or multiple copies; (b) Nrf2(nuclear factor erythroid 2-related factor 2), the principal transcription factor that het-erodimerizes with members of the small Maf family of transcription factors, binds tothe ARE, and recruits the general transcriptional machinery for expression of ARE-regulated genes (2); and (c) Keap1 (Kelch ECH associating protein 1), a cytosolicrepressor protein that binds to Nrf2, retains it in the cytoplasm, and promotes itsproteasomal degradation. It is thought that several critical cysteine residues in Keap1serve as the primary sensors for the stress signals and that their modification leads toconformational changes in Keap1, thereby producing liberated Nrf2. Since its ini-tial discovery by Yamamoto and his colleagues (3), it has become increasingly clearthat Keap1 plays a central role in regulating the protective response. It is also abun-dantly clear, that the downstream effector genes of this signaling pathway can affectresponses to a variety of environmental and cellular stresses. Beyond the classicalenvironmental stress response of catalyzing the detoxification of xenobiotics throughconjugation and trapping processes, genomic analyses indicate that gene familiesaffected by this transcription factor (a) provide direct antioxidants (4, 5), (b) en-code enzymes that directly inactivate oxidants (6), (c) increase levels of glutathione90 Kensler·Wakabayashi·BiswalAnnu. Rev. Pharmacol. Toxicol. 2007.47:89-116. Downloaded from arjournals.annualreviews.orgby University of North Carolina - Chapel Hill on 03/04/07. For personal use only.ANRV298-PA47-03 ARI 7 December 2006 15:6AREsMafCBP/p300Nrf2Keap1SH SHCul3Roc1E2UbUbUbUbNrf2Stressors / inducers• 15d-PGJ2• ER stress• ROS• NO• Diphenols, diamines• Michael acceptors• Isothiocyanates• Thiocarbamates• Dithiolethiones• Hydroperoxides• Trivalent arsenicals• Heavy metals• Vicinal dimercaptans• Conjugated polyenesKinasesProteasomedegradationCRM1ImportinCYTOPLASMNUCLEUSTarget gene
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