Cell survival responses to environmental stresses via the Keap1-Nrf2-ARE pathway

Thomas W. Kensler, Nobunao Wakabayashi, Shyam Biswal

Research output: Chapter in Book/Report/Conference proceedingChapter

Abstract

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.

Original languageEnglish (US)
Title of host publicationAnnual Review of Pharmacology and Toxicology
EditorsArthur Cho
Pages89-116
Number of pages28
DOIs
StatePublished - Feb 23 2007

Publication series

NameAnnual Review of Pharmacology and Toxicology
Volume47
ISSN (Print)0362-1642

Keywords

  • Antioxidant response element
  • Cytoprotection
  • Gene expression
  • Knockout mice
  • Oxidative stress

ASJC Scopus subject areas

  • Toxicology
  • Pharmacology

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  • Cite this

    Kensler, T. W., Wakabayashi, N., & Biswal, S. (2007). Cell survival responses to environmental stresses via the Keap1-Nrf2-ARE pathway. In A. Cho (Ed.), Annual Review of Pharmacology and Toxicology (pp. 89-116). (Annual Review of Pharmacology and Toxicology; Vol. 47). https://doi.org/10.1146/annurev.pharmtox.46.120604.141046