Keap1-null mutation leads to postnatal lethality due to constitutive Nrf2 activation
Keap1-null mutation leads to postnatal lethality due to constitutive Nrf2 activation
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DOI：
10.1038/ng1248
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发表时间：
2003-11-01
期刊：
影响因子：
30.8
通讯作者：
Yamamoto, M
中科院分区：
文献类型：
--
作者：
Wakabayashi, N;Itoh, K;Yamamoto, M
转录因子Nrf2（由Nfe2l2编码）调节一系列解毒和抗氧化基因，Keap1抑制Nrf2功能。当我们消融Keap1时，Keap1缺陷小鼠出生后死亡，可能是由于食管和前胃角化过度引起的营养不良。Nrf2活性影响几种鳞状上皮基因的表达水平。生物化学数据显示，在没有Keap 1的情况下，Nrf2在细胞核中组成性积累以刺激细胞保护基因的转录。与Nrf2缺陷小鼠的交配逆转了表型Keap1缺陷。这些实验表明，Keap1在细胞对氧化和外源性应激的反应中作用于Nrf2的上游。
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.