Keap1-null mutation leads to postnatal lethality due to constitutive Nrf2 activation

Nat Genet. 2003 Nov;35(3):238-45. doi: 10.1038/ng1248. Epub 2003 Sep 28.


Transcription factor Nrf2 (encoded by Nfe2l2) regulates a battery of detoxifying and antioxidant genes, and Keap1 represses Nrf2 function. When we ablated Keap1, Keap1-deficient mice died postnatally, probably from malnutrition resulting from hyperkeratosis in the esophagus and forestomach. Nrf2 activity affects the expression levels of several squamous epithelial genes. Biochemical data show that, without Keap1, Nrf2 constitutively accumulates in the nucleus to stimulate transcription of cytoprotective genes. Breeding to Nrf2-deficient mice reversed the phenotypic Keap1 deficiencies. These experiments show that Keap1 acts upstream of Nrf2 in the cellular response to oxidative and xenobiotic stress.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adaptor Proteins, Signal Transducing*
  • Animals
  • Carrier Proteins / genetics
  • Carrier Proteins / physiology*
  • Cytoskeletal Proteins*
  • DNA-Binding Proteins / metabolism*
  • Esophageal Diseases / genetics
  • Genes, Lethal*
  • Kelch-Like ECH-Associated Protein 1
  • Keratins / metabolism
  • Membrane Proteins / metabolism
  • Mice
  • Mice, Knockout
  • Mutation*
  • NF-E2-Related Factor 2
  • Stomach Diseases / genetics
  • Trans-Activators / metabolism*
  • Weaning


  • Adaptor Proteins, Signal Transducing
  • Carrier Proteins
  • Cytoskeletal Proteins
  • DNA-Binding Proteins
  • Keap1 protein, mouse
  • Kelch-Like ECH-Associated Protein 1
  • Membrane Proteins
  • NF-E2-Related Factor 2
  • Nfe2l2 protein, mouse
  • Trans-Activators
  • loricrin
  • Keratins