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

Thomas W Kensler1, Nobunao Wakabayashi, Shyam Biswal

  • 1Department of Environmental Health Sciences, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA. tkensler@jhsph.edu

Annual Review of Pharmacology and Toxicology
|September 14, 2006
PubMed

Insights

The Keap1-Nrf2-ARE pathway protects cells from stress. Nrf2 knockout mice show increased sensitivity to toxins, highlighting this pathway's crucial role in cellular defense against environmental damage.

Area of Science:

  • Toxicology
  • Molecular Biology
  • Cellular Stress Response

Background:

  • The Keap1-Nrf2-ARE signaling pathway is vital for cellular protection against endogenous and exogenous stresses.
  • Nrf2 (Nuclear factor erythroid 2-related factor 2) is a transcription factor regulated by Keap1 (Kelch-like ECH-associated protein 1).
  • This pathway controls the expression of numerous cytoprotective genes.

Purpose of the Study:

  • To review the key elements of the Keap1-Nrf2-ARE adaptive response.
  • To highlight the protective role of this pathway against acute and chronic cell injury.
  • To underscore the toxicological importance of Nrf2 using knockout mouse models.

Main Methods:

  • Review of scientific literature on Keap1-Nrf2-ARE signaling.
  • Analysis of data from Nrf2 knockout mouse studies.
  • Examination of cellular responses to oxidative, electrophilic, and environmental stresses.

Main Results:

  • Nrf2 knockout mice exhibit heightened sensitivity to hepatic, pulmonary, ovarian, and neurotoxic effects of various exposures.
  • Under stress, Nrf2 dissociates from Keap1, evades degradation, and upregulates cytoprotective genes.
  • This adaptive response is crucial for cell survival against environmental insults.

Conclusions:

  • The Keap1-Nrf2-ARE pathway is a critical defense mechanism against cellular damage.
  • Dysregulation or deficiency in this pathway significantly increases susceptibility to toxic agents.
  • Understanding this pathway is essential for developing strategies against environmental toxicity and carcinogens.

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