Critical Cysteine Residues of Kelch-Like ECH-Associated Protein 1 in Arsenic Sensing and Suppression of Nuclear Factor Erythroid 2-Related Factor 2

He, Xiaoqing; Ma, Qiang

doi:10.1124/jpet.109.160465

Cited by 66 publications

(46 citation statements)

References 32 publications

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“…These effects are eliminated in the miR-340 mimics combined with inhibitors group (Figure 5, 6A). According to previous findings, Nrf2 expression is mainy regulated by Nrf2 interaction with Kelch-like ECH-associated protein 1 (Keap1), which leads to degradation of Nrf2 by the ubiquitin-proteasome pathway (He and Ma, 2010), further studies to assess whether MiR-340 inhibits Nrf2 expression through a Keap1-dependent manner were warranted…”

Section: Discussionmentioning

confidence: 99%

miR-340 Reverses Cisplatin Resistance of Hepatocellular Carcinoma Cell Lines by Targeting Nrf2-dependent Antioxidant Pathway

Shi

Chen²,

Wu³

et al. 2015

Asian Pacific Journal of Cancer Prevention

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Section: Discussionmentioning

confidence: 99%

miR-340 Reverses Cisplatin Resistance of Hepatocellular Carcinoma Cell Lines by Targeting Nrf2-dependent Antioxidant Pathway

Shi

Chen²,

Wu³

et al. 2015

Asian Pacific Journal of Cancer Prevention

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“…Degradation is mediated through the Keap1/Cul3 dependent E3-controlled ubiquitination and subsequent proteasomal degradation of Nrf2 [16]. Keap1 contains ~25 cysteine residues, whereas Nrf2 has 7 highly conserved cysteine residues [26,27]. Electrophilic inducers interact with the thiol groups of critical cysteine residues in both Keap1 and Nrf2 to trigger inhibition of Nrf2 ubiquitination and degradation.…”

Section: Discussionmentioning

confidence: 99%

“…Nrf2 and its binding protein Keap1 are redox sensors. Inducers, such as phenolic antioxidants, Michael reaction acceptors, and transition metals, modify critical cysteine residues in Keap1 and Nrf2 leading to suppression of Nrf2 degradation and consequently, activation of Nrf2 [25][26][27][28]. Activated Nrf2 translocates into the nucleus, dimerizes with a small Maf protein, and binds to a common DNA sequence called "antioxidant responsive element" (ARE) to up-regulate the transcription of a battery of cytoprotective enzymes/proteins [17].…”

Section: Factors Influencingmentioning

confidence: 99%

Disruption of Nrf2 Synergizes with High Glucose to Cause Heightened Myocardial Oxidative Stress and Severe Cardiomyopathy in Diabetic Mice

2013

J Diabetes Metab

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High glucose-induced oxidative stress is a major contributing mechanism to the development of diabetic cardiomyopathy. Nrf2 is an emerging critical regulator of cellular defense against oxidative damage. The role of Nrf2 in diabetic cardiomyopathy was investigated in vivo. Streptozotocin (STZ) induced diabetes in Nrf2 knockout (KO) mice that rapidly progressed to severe conditions with high mortality within two weeks of injection; whereas, in wild type (WT) mice, diabetes was less severe with no death. Severe myocardial lesions were observed in diabetic KO mice that had high, sublethal levels of blood glucose including: (a) irregular myocardial arrangements, myofibrillar discontinuation, and cell death; (b) reduced electron density, discontinuation of myocardial fibers, and mitochondrial damage; and (c) markedly reduced contractility of the cardiomyocytes to β-agonist stimulation. Parallel to severe cardiomyopathy, the diabetic KO hearts showed: (a) increased apoptosis as revealed by TUNEL and PARP1 cleavage assays; (b) infiltration of granulocytes and macrophages as well as fibrosis indicating robust inflammatory response; and (c) heightened oxidative stress as evidenced by increased levels of 8-hydroxydeoxyquanine, free malondialdehyde, and 3-nitrotyrosine. Increased oxidative stress in the KO hearts was attributed to decrease or loss of the basal and induced expression of Nrf2-dependent cytoprotective genes. Our findings demonstrate that loss of Nrf2 function synergizes with high glucose to cause heightened oxidative stress in the heart leading to severe diabetic cardiomyopathy.

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“…Inducers are structurally diverse and have few common properties, except for their ability to modify -SH at rates closely correlated with their potency for induction of NQO1 (53). Evidence for binding of inducers to Keap1 cysteine thiols was provided using labeled inducers, stoichiometry, ultraviolet spectroscopy, mass spectrometry, and mutational studies (53)(54)(55)(56). The IVR region contains multiple cysteine residues that were frequently labeled by inducers, in particular, C273, C288, and C297.…”

Section: Activation Of Nrf2 By Are Inducersmentioning

confidence: 99%

Role of Nrf2 in Oxidative Stress and Toxicity

2013

Annu. Rev. Pharmacol. Toxicol.

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3,614

2,618

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Organismal life encounters reactive oxidants from internal metabolism and environmental toxicant exposure. Reactive oxygen and nitrogen species cause oxidative stress and are traditionally viewed as being harmful. On the other hand, controlled production of oxidants in normal cells serves useful purposes to regulate signaling pathways. Reactive oxidants are counterbalanced by complex antioxidant defense systems regulated by a web of pathways to ensure that the response to oxidants is adequate for the body's needs. A recurrent theme in oxidant signaling and antioxidant defense is reactive cysteine thiol-based redox signaling. The nuclear factor erythroid 2-related factor 2 (Nrf2) is an emerging regulator of cellular resistance to oxidants. Nrf2 controls the basal and induced expression of an array of antioxidant response element-dependent genes to regulate the physiological and pathophysiological outcomes of oxidant exposure. This review discusses the impact of Nrf2 on oxidative stress and toxicity and how Nrf2 senses oxidants and regulates antioxidant defense.

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Critical Cysteine Residues of Kelch-Like ECH-Associated Protein 1 in Arsenic Sensing and Suppression of Nuclear Factor Erythroid 2-Related Factor 2

Cited by 66 publications

References 32 publications

miR-340 Reverses Cisplatin Resistance of Hepatocellular Carcinoma Cell Lines by Targeting Nrf2-dependent Antioxidant Pathway

miR-340 Reverses Cisplatin Resistance of Hepatocellular Carcinoma Cell Lines by Targeting Nrf2-dependent Antioxidant Pathway

Disruption of Nrf2 Synergizes with High Glucose to Cause Heightened Myocardial Oxidative Stress and Severe Cardiomyopathy in Diabetic Mice

Role of Nrf2 in Oxidative Stress and Toxicity

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