Chemistry of the Cysteine Sensors in Kelch-Like ECH-Associated Protein 1

Holland, Ryan J.; Fishbein, James C.

doi:10.1089/ars.2010.3273

Cited by 96 publications

(73 citation statements)

References 66 publications

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“…A widely accepted model for Nrf2 nuclear accumulation describes that a modification of the Keap1 cysteines leads directly to the dissociation of the Keap1-Nrf2 complex (33). Recently, one study suggested that Keap1 can be S-sulfhydrated at Cys151, which stimulates the dissociation of Nrf2 to enable its translocation to the nucleus (34).…”

Section: Discussionmentioning

confidence: 99%

Hydrogen Sulfide Induces Keap1 S-sulfhydration and Suppresses Diabetes-Accelerated Atherosclerosis via Nrf2 Activation

et al. 2016

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Hydrogen sulfide (H2S) has been shown to have powerful antioxidative and anti-inflammatory properties that can regulate multiple cardiovascular functions. However, its precise role in diabetes-accelerated atherosclerosis remains unclear. We report here that H2S reduced aortic atherosclerotic plaque formation with reduction in superoxide (O2−) generation and the adhesion molecules in streptozotocin (STZ)-induced LDLr−/− mice but not in LDLr−/−Nrf2−/− mice. In vitro, H2S inhibited foam cell formation, decreased O2− generation, and increased nuclear factor erythroid 2–related factor 2 (Nrf2) nuclear translocation and consequently heme oxygenase 1 (HO-1) expression upregulation in high glucose (HG) plus oxidized LDL (ox-LDL)–treated primary peritoneal macrophages from wild-type but not Nrf2−/− mice. H2S also decreased O2− and adhesion molecule levels and increased Nrf2 nuclear translocation and HO-1 expression, which were suppressed by Nrf2 knockdown in HG/ox-LDL–treated endothelial cells. H2S increased S-sulfhydration of Keap1, induced Nrf2 dissociation from Keap1, enhanced Nrf2 nuclear translocation, and inhibited O2− generation, which were abrogated after Keap1 mutated at Cys151, but not Cys273, in endothelial cells. Collectively, H2S attenuates diabetes-accelerated atherosclerosis, which may be related to inhibition of oxidative stress via Keap1 sulfhydrylation at Cys151 to activate Nrf2 signaling. This may provide a novel therapeutic target to prevent atherosclerosis in the context of diabetes.

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Section: Discussionmentioning

confidence: 99%

Hydrogen Sulfide Induces Keap1 S-sulfhydration and Suppresses Diabetes-Accelerated Atherosclerosis via Nrf2 Activation

et al. 2016

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“…The best known is the Cullin 3 (Cul3) RING-box 1 (RBX1) E3 ubiquitin ligase complex, which needs the substrate adaptor protein Kelch-like ECHassociated protein 1 (Keap1) to ubiquitinate Nrf2 (Cullinan et al, 2004;Kobayashi et al, 2004;Zhang et al, 2004). Keap1 is a cysteine-rich regulatory protein located in the cytoplasm (Itoh et al, 1999;Holland and Fishbein, 2010). Keap1 dimerizes and binds Cul3 through its BTB domain (Furukawa and Xiong, 2005), while its Kelch domain is able to interact with the Neh2 domain of Nrf2 (Itoh et al, 1999;McMahon et al, 2006).…”

Section: Nrf2 Structure and Regulationmentioning

confidence: 99%

“…Under stress conditions, certain Keap1 cysteine residues are chemically modified, which prevents Nrf2 ubiquitination and degradation, allowing its stabilization and the transcription of its target genes (Holland and Fishbein, 2010) (Figure 1B). It has also been described that some electrophilic lipids, such as the cyclopentenone prostaglandin, 15-deoxy-Δ 12,14 -prostaglandin J 2 (which serves as a model to study the effects of lipid peroxidation products derived by the reaction of reactive oxygen/ nitrogen species with unsaturated fatty acids), are able to induce Nrf2 by modifying thiol groups of Keap1 (Levonen et al, 2004).…”

Section: Nrf2 Structure and Regulationmentioning

confidence: 99%

Nrf2 activation in the treatment of neurodegenerative diseases: a focus on its role in mitochondrial bioenergetics and function

Esteras¹,

Dinkova‐Kostova²,

Abramov³

2016

Biological Chemistry

139

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Abstract:The nuclear factor erythroid-derived 2 (NF-E2)-related factor 2 (Nrf2) is a transcription factor wellknown for its function in controlling the basal and inducible expression of a variety of antioxidant and detoxifying enzymes. As part of its cytoprotective activity, increasing evidence supports its role in metabolism and mitochondrial bioenergetics and function. Neurodegenerative diseases are excellent candidates for Nrf2-targeted treatments. Most neurodegenerative conditions such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, frontotemporal dementia and Friedreich's ataxia are characterized by oxidative stress, misfolded protein aggregates, and chronic inflammation, the common targets of Nrf2 therapeutic strategies. Together with them, mitochondrial dysfunction is implicated in the pathogenesis of most neurodegenerative disorders. The recently recognized ability of Nrf2 to regulate intermediary metabolism and mitochondrial function makes Nrf2 activation an attractive and comprehensive strategy for the treatment of neurodegenerative disorders. This review aims to focus on the potential therapeutic role of Nrf2 activation in neurodegeneration, with special emphasis on mitochondrial bioenergetics and function, metabolism and the role of transporters, all of which collectively contribute to the cytoprotective activity of this transcription factor.

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“…The cellular sensor protein Kelch-like ECH-associated protein 1 (Keap1) contains large numbers of sulfhydryl groups that can be modified by oxidants and electrophiles [10,11] . Under basal conditions, Keap1 associates with the key transcriptional factor nuclear factor erythroid 2-related factor 2 (Nrf2) and targets it for degradation [12] . When Keap1 is modified by either oxidative or electrophilic reagents, proteolysis is inhibited, and the dissociated Nrf2 translocates to the nucleus, binds to ARE, and promotes phase II enzyme gene expression [12] .…”

Section: Introductionmentioning

confidence: 99%

“…Under basal conditions, Keap1 associates with the key transcriptional factor nuclear factor erythroid 2-related factor 2 (Nrf2) and targets it for degradation [12] . When Keap1 is modified by either oxidative or electrophilic reagents, proteolysis is inhibited, and the dissociated Nrf2 translocates to the nucleus, binds to ARE, and promotes phase II enzyme gene expression [12] . Therefore, oxidants and electrophiles might initiate the inducer signal by modifying Keap1 sulfhydryl groups, which can be further transduced by the Keap1-Nrf2 signaling pathway to activate cellular ARE.…”

Section: Introductionmentioning

confidence: 99%

Selective estrogen receptor modulator BC-1 activates antioxidant signaling pathway in vitro via formation of reactive metabolites

Mai

Liu

et al. 2013

Acta Pharmacol Sin

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Aim: Benzothiophene compounds are selective estrogen receptor modulators (SERMs), which are recently found to activate antioxidant signaling. In this study the molecular mechanisms of antioxidant signaling activation by benzothiophene compound BC-1 were investigated. Methods: HepG2 cells were stably transfected with antioxidant response element (ARE)-luciferase reporter (HepG2-ARE cells). The expression of nuclear factor erythroid 2-related factor 2 (Nrf2) in HepG2-ARE cells was suppressed using siRNA. The metabolites of BC-1 in rat liver microsome incubation were analyzed using LC-UV and LC-MS. Results: Addition of BC-1 (5 μmol/L) in HepG2-ARE cells resulted in a 17-fold increase of ARE-luciferase activity. Pretreatment with the estrogen receptor agonist E 2 (5 μmol/L) or antagonist ICI 182,780 (5 μmol/L) did not affect BC-1-induced ARE-luciferase activity. However, transfection of the cells with anti-Nrf2 siRNA suppressed this effect by 79%. Addition of BC-1 in rat microsome incubation resulted in formation of di-quinone methides and o-quinones, followed by formation of GSH conjugates. BC-1 analogues with hydrogen (BC-2) or fluorine (BC-3) at the 4′ position did not form the di-quinone methides. Both BC-2 and BC-3 showed comparable estrogenic activity with BC-1, but did not induce ARE-luciferase activity in HepG2-ARE cells. Conclusion: Benzothiophene compound BC-1 activates ARE signaling via reactive metabolite formation that is independent of estrogen receptors.

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Chemistry of the Cysteine Sensors in Kelch-Like ECH-Associated Protein 1

Cited by 96 publications

References 66 publications

Hydrogen Sulfide Induces Keap1 S-sulfhydration and Suppresses Diabetes-Accelerated Atherosclerosis via Nrf2 Activation

Hydrogen Sulfide Induces Keap1 S-sulfhydration and Suppresses Diabetes-Accelerated Atherosclerosis via Nrf2 Activation

Nrf2 activation in the treatment of neurodegenerative diseases: a focus on its role in mitochondrial bioenergetics and function

Selective estrogen receptor modulator BC-1 activates antioxidant signaling pathway in vitro via formation of reactive metabolites

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