ArticleMolecular and cellular biology2010
Genetic analysis of cytoprotective functions supported by graded expression of Keap1.
Article in Molecular and cellular biology, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 117 papers.
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Who cites it
117 citing papers in PubMed, 223 citations in OpenAlex.
- Obesity-associated unfolded protein response, oxidative stress, and NRF2 signaling.International journal of obesity (2005) · 2026Review
- Nrf2 modulates cytosolic and mitochondrial calcium signal.Redox biology · 2026Article
- Inducible kidney-selective knockdown of Cyp27b1 does not compromise calcium and bone homeostasis.Journal of endocrinological investigation · 2026Article
- The electrophilic metabolite of kynurenine, kynurenine-CKA, targets C151 in Keap1 to derepress Nrf2.bioRxiv : the preprint server for biology · 2025Article
- Modulation of Nrf2 and Mitochondrial Function: Pharmacological Implications.Pharmaceuticals (Basel, Switzerland) · 2025Review
- Stress-NRF2 response axis polarizes tumor macrophages and undermines immunotherapy.Journal for immunotherapy of cancer · 2025Article
- Efficacy of Nrf2 activation in a proteinuric Alport syndrome mouse model.Life science alliance · 2025Article
- NRF2 activation in the heart induces glucose metabolic reprogramming and reduces cardiac dysfunction via upregulation of the pentose phosphate pathway.Cardiovascular research · 2025Article
- Model organisms for investigating the functional involvement of NRF2 in non-communicable diseases.Redox biology · 2025Review
- Mechanism of valproic acid-induced hepatic steatosis via enhancing NRF2-FATP2-mediated fatty acid uptake.Theranostics · 2025Article
- Role of NRF2 in Pathogenesis of Alzheimer's Disease.Antioxidants (Basel, Switzerland) · 2024Review
- Review
- Transcription Factor NRF2 in Shaping Myeloid Cell Differentiation and Function.Advances in experimental medicine and biology · 2024Review
- Hemorrhage-activated NRF2 in tumor-associated macrophages drives cancer growth, invasion, and immunotherapy resistance.The Journal of clinical investigation · 2023Article
- Sulforaphane decreases serum selenoprotein P levels through enhancement of lysosomal degradation independent of Nrf2.Communications biology · 2023Article
- Explicit mechanistic insights of Prosopis juliflora extract in streptozotocin-induced diabetic rats at the molecular level.Saudi pharmaceutical journal : SPJ : the official publication of the Saudi Pharmaceutical Society · 2023Article
- Forced Hepatic Expression of NRF2 or NQO1 Impedes Hepatocyte Lipid Accumulation in a Lipodystrophy Mouse Model.International journal of molecular sciences · 2023Article
- Distinct Nrf2 Signaling Thresholds Mediate Lung Tumor Initiation and Progression.Cancer research · 2023Article
- Nrf2-Mediated Antioxidant Defense and Thyroid Hormone Signaling: A Focus on Cardioprotective Effects.Antioxidants (Basel, Switzerland) · 2023Review
- Nrf2 Activation Does Not Protect from Aldosterone-Induced Kidney Damage in Mice.Antioxidants (Basel, Switzerland) · 2023Article
57 more citing papers are in PubMed but not listed here.
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Authors and funding
6 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Keap1 regulates Nrf2 activity in response to xenobiotic and oxidative stresses. Nrf2 is an essential regulator of cytoprotective genes. Keap1-null mice are lethal by weaning age due to malnutrition caused by severe hyperkeratosis of the upper digestive tract. Analysis of Keap1::Nrf2 double mutant mice revealed that currently recognizable phenotypes of Keap1-null mice are all attributable to constitutive activation of Nrf2. We previously reported that hepatocyte-specific Keap1 knockout (Keap1(flox/-)::Albumin-Cre) mice are viable and more resistant to acute toxicity of acetaminophen (APAP). In the current study, we found that the floxed Keap1 allele is hypomorphic and that Keap1 expression was decreased in all examined tissues of Keap1(flox/-) mice. Taking advantage of the hypomorphic phenotype of Keap1(flox/-) mice, we examined the effects of graded reduction of Keap1 expression in adult mice. When challenged with APAP, Keap1(flox/-) mice were more protected from mortality than wild-type and even Keap1(flox/-)::Albumin-Cre mice. In contrast, a decrease in Keap1 levels to less than 50% resulted in increased mortality in a study of 2-year-old mice. These results support our contention that the benefits of Nrf2 activation in acute toxicity are hormetic and that constitutive Nrf2 activation beyond a certain threshold is rather disadvantageous to long-term survival.
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