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

Nobunao Wakabayashi, Ken Itoh, Junko Wakabayashi, Hozumi Motohashi, Shuhei Noda, Satoru Takahashi, Sumihisa Imakado, Tomoe Kotsuji, Fujio Otsuka, Dennis R. Roop, Takanori Harada, James Douglas Engel, Masayuki Yamamoto

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563 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)238-245
Number of pages8
JournalNature Genetics
Volume35
Issue number3
DOIs
Publication statusPublished - 2003 Nov

ASJC Scopus subject areas

  • Genetics

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    Wakabayashi, N., Itoh, K., Wakabayashi, J., Motohashi, H., Noda, S., Takahashi, S., Imakado, S., Kotsuji, T., Otsuka, F., Roop, D. R., Harada, T., Engel, J. D., & Yamamoto, M. (2003). Keap1-null mutation leads to postnatal lethality due to constitutive Nrf2 activation. Nature Genetics, 35(3), 238-245. https://doi.org/10.1038/ng1248