TY - JOUR
T1 - Keap1-null mutation leads to postnatal lethality due to constitutive Nrf2 activation
AU - Wakabayashi, Nobunao
AU - Itoh, Ken
AU - Wakabayashi, Junko
AU - Motohashi, Hozumi
AU - Noda, Shuhei
AU - Takahashi, Satoru
AU - Imakado, Sumihisa
AU - Kotsuji, Tomoe
AU - Otsuka, Fujio
AU - Roop, Dennis R.
AU - Harada, Takanori
AU - Engel, James Douglas
AU - Yamamoto, Masayuki
N1 - Funding Information:
We are grateful to O. Nakajima, F. Irie, M. Osaki, S. Kawauchi, X. Pan, S. Masuda, N. Kaneko, H. Ohkawa and R. Kawai for help; K-C. Lim, M. Kobayashi, K. Igarashi, T. O’Connor, T. Hosoya, M. Nose, Y. Kawachi and T. W. Kensler for useful suggestions; and J. D. Hayes and K. Satoh for antibodies. This work was supported by a grant from the US National Institutes of Health (J.D.E.) and grants from the Ministry of Education, Science, Sports and Culture (K.I., H.M. and M.Y.), JST-ERATO (M.Y.), JST-CREST (H.M.) and PROBRAIN (H.M. and S.T.). N.W. was a JSPS-RFTF postdoctoral fellow.
PY - 2003/11
Y1 - 2003/11
N2 - 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.
AB - 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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U2 - 10.1038/ng1248
DO - 10.1038/ng1248
M3 - Article
C2 - 14517554
AN - SCOPUS:0242329881
SN - 1061-4036
VL - 35
SP - 238
EP - 245
JO - Nature Genetics
JF - Nature Genetics
IS - 3
ER -
