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Keap1-null mutation leads to postnatal lethality due to constitutive Nrf2 activation
Nobunao Wakabayashi1, Ken Itoh, Junko Wakabayashi
1Center for Tsukuba Advanced Research Alliance, University of Tsukuba, 1-1-1 Tennoudai, Tsukuba 305-8577, Japan.
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.
Insights
Ablating Keap1 in mice led to postnatal death due to hyperkeratosis, but this was reversed by Nrf2 deficiency. This demonstrates Keap1 acts upstream of Nrf2 in stress response.
Area of Science:
- Molecular Biology
- Cellular Biology
- Toxicology
Background:
- Nuclear factor erythroid 2-related factor 2 (Nrf2) controls antioxidant and detoxifying genes.
- Kelch-like ECH-associated protein 1 (Keap1) normally inhibits Nrf2 activity.
- Nrf2 influences the expression of squamous epithelial genes.
Purpose of the Study:
- To investigate the functional relationship between Keap1 and Nrf2 in vivo.
- To elucidate the role of Keap1 in regulating Nrf2 activity and its downstream effects.
Main Methods:
- Keap1 gene ablation in mice.
- Generation of Keap1-deficient and Nrf2-deficient mouse models.
- Phenotypic analysis of resulting mouse models.
- Biochemical assays to assess Nrf2 nuclear localization and transcriptional activity.
Main Results:
- Keap1-deficient mice exhibited postnatal lethality, likely due to malnutrition from esophageal and forestomach hyperkeratosis.
- Constitutive nuclear accumulation of Nrf2 was observed in the absence of Keap1, leading to increased transcription of cytoprotective genes.
- The adverse phenotypes of Keap1 deficiency were ameliorated by concurrent Nrf2 deficiency.
Conclusions:
- Keap1 functions upstream of Nrf2, acting as a critical repressor of Nrf2 activity.
- The Keap1-Nrf2 pathway is essential for maintaining cellular homeostasis and preventing pathologies associated with oxidative and xenobiotic stress.
