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Article
Nature Genetics  35, 238 - 245 (2003)
Published online: 28 September 2003; | doi:10.1038/ng1248

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

Nobunao Wakabayashi1, Ken Itoh1, 2, Junko Wakabayashi1, Hozumi Motohashi1, Shuhei Noda1, Satoru Takahashi3, Sumihisa Imakado4, Tomoe Kotsuji4, Fujio Otsuka4, Dennis R Roop5, Takanori Harada6, James Douglas Engel7 & Masayuki Yamamoto1, 2, 3

1  Center for Tsukuba Advanced Research Alliance, University of Tsukuba, 1-1-1 Tennoudai, Tsukuba 305-8577, Japan.

2  ERATO-JST, University of Tsukuba, 1-1-1 Tennoudai, Tsukuba 305-8577, Japan.

3  Institutes of Basic Medical Sciences, University of Tsukuba, 1-1-1 Tennoudai, Tsukuba 305-8577, Japan.

4  Clinical Medical Sciences, University of Tsukuba, 1-1-1 Tennoudai, Tsukuba 305-8577, Japan.

5  Departments of Molecular and Cellular Biology and Dermatology, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA.

6  The Institute of Environmental Toxicology 4321 Uchimoriya-cho, Mitsukaido-shi, Ibaraki 303-0043, Japan.

7  Department of Cell and Developmental Biology, University of Michigan Medical School, 1335 Catherine, Ann Arbor, Michigan 48109, USA.

Correspondence should be addressed to Masayuki Yamamoto masi@tara.tsukuba.ac.jp
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.

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Nature Genetics
ISSN: 1061-4036
EISSN: 1546-1718
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