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

Wakabayashi, Nobunao; Itoh, Ken; Wakabayashi, Junko; Motohashi, Hozumi; Noda, Shinshi; Takahashi, Satoru; Imakado, Sumihisa; Kotsuji, Tomoe; Otsuka, Fujio; Roop, Dennis R.; Harada, Takanori; Engel, James Douglas; Yamamoto, Masayuki

doi:10.1038/ng1248

Cited by 818 publications

(777 citation statements)

References 34 publications

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“…As induction of AKR1C1͞2 by Target1 siRNA was quantitatively similar to that obtained by using Sul, it appears unlikely that a regulated limiting step exists downstream of Keap1. These results are consistent with the observed up-regulation of NQO1, GST, GCLC, and GCLM in the keap1 Ϫ/Ϫ mouse (33). However, our findings and those from the keap1 Ϫ/Ϫ mouse are surprising given the reports that release of Nrf2 from Keap1 and͞or nuclear translocation of Nrf2 are controlled during oxidative stress by PKC (24,25) and during endoplasmic reticulum stress by PKR-like endoplasmic reticulum-resident kinase (PERK) (27).…”

Section: Discussionsupporting

confidence: 60%

Utility of siRNA against Keap1 as a strategy to stimulate a cancer chemopreventive phenotype

Devling

Lindsay²,

McLellan³

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

117

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A duplex 21 nucleotide small interfering RNA (siRNA) against human Keap1 is described that represents a unique class of cancer chemopreventive agent. This siRNA can knockdown Keap1 mRNA and thereby relieve negative regulation of nuclear factor erythroid 2 p45-related factor 2 (Nrf2)-mediated gene expression. The siRNA lowered endogenous Keap1 mRNA to <30% of control levels between 24 and 72 h after transfection in human HaCaT keratinocyte cells and was capable of blocking ectopic expression of FLAG-tagged human Keap1 protein but not that of ectopic V5-tagged mouse Keap1 protein. Transfection of human HaCaT cells with Keap1 siRNA markedly enhanced endogenous levels of nuclear factor erythroid 2 p45-related factor 2 (Nrf2) protein and increased transcription of an antioxidant response element-driven reporter gene by 2.3-fold. Furthermore, 48 h after transfection of these cells with Keap1 siRNA, expression of aldo-keto reductase 1C1͞2 and the glutamate cysteine ligase catalytic and modifier subunits was elevated between 5-and 14-fold. A modest increase of 3-fold in NAD(P)H:quinone oxidoreductase 1 was also observed. The Keap1 siRNA produced a 1.75-fold increase in intracellular glutathione 48 h after transfection. Thus, antagonism of Keap1 by siRNA can be used to preadapt human cells to oxidative stress without the need to expose them to redox stressors.antioxidant ͉ chemoprevention ͉ glutathione ͉ nuclear factor erythroid 2 p45-related factor 2 ͉ aldo-keto reductase

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Section: Discussionsupporting

confidence: 60%

Utility of siRNA against Keap1 as a strategy to stimulate a cancer chemopreventive phenotype

Devling

Lindsay²,

McLellan³

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

117

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“…In contrast, excessive or unrestrained activity of Nrf2 system has been shown to have adverse consequences. For instance unrestrained activation of Nrf2 pathway leads to post-natal mortality in Keap1knock out mice [50] and worsening of insulin resistance, adipose tissue contraction, weight loss, and hepatic steatosis in Keap1 knock down leptin-deficient mice [51] Nrf2 is held in the cell cytoplasm as an inactive complex by Keap1 (Kelch-like ECH-associated protein 1) a repressor molecule which mediates Nrf2 degradation by serving as an adaptor for Cul3 Rbx1 E3 ligase complex. Keap1 molecule contains a number of reactive cysteine residues that serve as sensors of the intra-cellular redox state.…”

Section: Discussionmentioning

confidence: 99%

Dose-dependent deleterious and salutary actions of the Nrf2 inducer dh404 in chronic kidney disease

Vaziri¹,

Liu²,

Farzaneh³

et al. 2015

Free Radical Biology and Medicine

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Oxidative stress and inflammation play a central role in progression and complications of CKD and are, in part, due to impairment of the Nrf2 system which regulates expression of antioxidant and detoxifying molecules. Natural Nrf2 inducing phytochemicals have been shown to ameliorate kidney disease in experimental animals. However due to adverse outcomes clinical trial of synthetic Nrf2 activator, bardoxolone methyl (BARD), in CKD patients was terminated. BARD activates Nrf2 via 2 covalent modification of reactive cysteine residues in Nrf2 repressor molecule, Keap-1. In addition to Nrf2, Keap1 suppresses IKKB, the positive regulator of NF k B. Treatment with BARD analog, dh404, at 5-20 mg/kg/day in diabetic obese Zucker rats exacerbates whereas its use at 2 mg/kg/day in 5/6 nephrectomized rats attenuates CKD progression. We, therefore, hypothesized that deleterious effects of high dose BARD are mediated by activation of NF k B.CKD (5/6 nephrectomized) rats were randomized to receive dh404 (2 or 10mg/kg/day) or vehicle for 12 weeks. Vehicle-treated group exhibited glomerulosclerosis, interstitial fibrosis and inflammation, activation of NF k B, upregulation of oxidative, inflammatory and fibrotic pathways, and suppression of Nrf2 activity and its key target gene products. Treatment with low dose dh404 restored Nrf2 activity and expression of its target genes, attenuated activation of NF k B and fibrotic pathways, and reduced glomerulosclerosis, interstitial fibrosis and inflammation. In contrast treatment with high dh404 dosage intensified proteinuria, renal dysfunction and histological abnormalities, amplified up-regulations of NF k B and fibrotic pathways, and suppression of Nrf2 system. Thus therapy with BARD analogs exerts a dose-dependent dimorphic impact on CKD progression.

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“…Indeed, cells with double-strand DNA breaks (shown by H2AX phosphorylation) accumulate in the vicinity of the infected macrophages starting between 2 and 4 months post infection. Besides, constitutive activation of transcription factor Nrf2 by oxidative stress may directly induce squamous cell metaplasia (Wakabayashi et al, 2003). Second, normally proliferation of cells with DNA damage would have been blocked through G2/M checkpoint activation and those cells would either persist indefinitely in the absence of the 'promotion' signal or would be eliminated through p53-mediated pro-apoptotic pathway.…”

Section: Discussionmentioning

confidence: 99%

Lung carcinogenesis induced by chronic tuberculosis infection: the experimental model and genetic control

et al. 2009

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Coexistence of pulmonary tuberculosis (TB) and lung cancer in clinic poses significant challenges for the diagnostic and treatment of both diseases. Although association of chronic inflammation and cancer is welldocumented, causal relationship between TB infection and lung cancer are not understood. We present experimental evidence that chronic TB infection induces cell dysplasia and squamous cell carcinoma (SCC) in a lung-specific manner. First, squamous cell aggregates consistently appeared within the lung tissue associated with chronic TB lesions, and in some cases resembled SCCs. A transplantable tumor was established after the transfer of cells isolated from TB lung lesions into syngeneic recipients. Second, the (Mycobacterium tuberculosis) MTB-infected macrophages play a pivotal role in TBinduced carcinogenesis by inducing DNA damage in their vicinity and by the production of a potent epidermal growth factor epiregulin, which may serve as a paracrine survival and growth factor responsible for squamous metaplasia and tumorigenesis. Third, lung carcinogenesis during the course of chronic TB infection was more pronounced in animals with severe lung tissue damage mediated by TB-susceptibility locus sst1. Together, our experimental findings showed a causal link between pulmonary TB and lung tumorigenesis and established a genetic model for further analysis of carcinogenic mechanisms activated by TB infection.

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

Cited by 818 publications

References 34 publications

Utility of siRNA against Keap1 as a strategy to stimulate a cancer chemopreventive phenotype

Utility of siRNA against Keap1 as a strategy to stimulate a cancer chemopreventive phenotype

Dose-dependent deleterious and salutary actions of the Nrf2 inducer dh404 in chronic kidney disease

Lung carcinogenesis induced by chronic tuberculosis infection: the experimental model and genetic control

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