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Cell Survival Responses to Environmental Stresses Via the Keap1-Nrf2-ARE Pathway.

Kensler TW, Wakabayashi N, Biswal S

Department of Environmental Health Services, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205 tkensler@jhsph.edu.

Keap1-Nrf2-ARE signaling plays a significant role in protecting cells from endogenous and exogenous stresses. The development of Nrf2 knockout mice has provided key insights into the toxicological importance of this pathway. These mice are more sensitive to the hepatic, pulmonary, ovarian, and neurotoxic consequences of acute exposures to environmental agents and drugs, inflammatory stresses, as well as chronic exposures to cigarette smoke and other carcinogens. Under quiescent conditions, the transcription factor Nrf2 interacts with the actin-anchored protein Keap1, largely localized in the cytoplasm. This quenching interaction maintains low basal expression of Nrf2-regulated genes. However, upon recognition of chemical signals imparted by oxidative and electrophilic molecules, Nrf2 is released from Keap1, escapes proteasomal degradation, translocates to the nucleus, and transactivates the expression of several dozen cytoprotective genes that enhance cell survival. This review highlights the key elements in this adaptive response to protection against acute and chronic cell injury provoked by environmental stresses. Expected online publication date for the Annual Review of Pharmacology and Toxicology Volume 47 is January 6, 2007. Please see http://www.annualreviews.org/catalog/pub_dates.asp for revised estimates.

Published 13 September 2006 in Annu Rev Pharmacol Toxicol.
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