Mechanism of Chemical Activation of Nrf2

Li, Yun; Paonessa, Joseph D.; Zhang, Yuesheng

doi:10.1371/journal.pone.0035122

Cited by 138 publications

(109 citation statements)

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“…Consistent with these observations, several reports have shown that modification of Cys-151 inhibits the Keap1-Cul3 interface and prevents ubiquitination of Nrf2 (30,41). It should be noted that there are a couple of reports that disagree with this model (46,47). For instance, the Keap1-Cul3 complex does not dissociate upon exposure to 5,6-dihydrocyclopenta-1,2-dithiole-3-thione or sulforaphane (46).…”

mentioning

confidence: 73%

“…It should be noted that there are a couple of reports that disagree with this model (46,47). For instance, the Keap1-Cul3 complex does not dissociate upon exposure to 5,6-dihydrocyclopenta-1,2-dithiole-3-thione or sulforaphane (46). Similarly, a live-cell imaging analysis showed no dissociation of the Keap1-Cul3 complex upon exposure to 1-[2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oyl] (CDDO), sulforaphane, sulfoxythiocarbamate alkyne, or hydrogen peroxide (47).…”

Section: Minireview: Stress Response By the Keap1-nrf2 Systemmentioning

confidence: 95%

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Stress-sensing mechanisms and the physiological roles of the Keap1–Nrf2 system during cellular stress

Suzuki

Yamamoto

2017

Journal of Biological Chemistry

337

272

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Edited by Ruma BanerjeeTranscription factor Nrf2 (NF-E2-related factor 2) is a master regulator of cellular responses against environmental stresses. Nrf2 induces the expression of detoxification and antioxidant enzymes and suppresses the induction of pro-inflammatory cytokine genes. Keap1 (Kelch-like ECH-associated protein 1) is an adaptor subunit of Cullin 3-based E3 ubiquitin ligase. Keap1 regulates the activity of Nrf2 and acts as a sensor for oxidative and electrophilic stresses. In this review, we discuss the molecular mechanisms by which the Keap1-Nrf2 system senses and regulates the cellular response to environmental stresses. In particular, we focus on the multiple stress-sensing mechanisms of Keap1 and novel regulatory functions of Nrf2.Our body is equipped with a defense system that up-regulates the expression levels of cytoprotective enzyme genes. Nrf2 is the central player in the inducible expression of cellular defense enzymes (1, 2). Nrf2 belongs to the CNC (cap-n-collar) subfamily of basic region-leucine zipper-type transcription factors (3). Nrf2 dimerizes with one of the small Maf proteins (sMaf). The Nrf2-sMaf heterodimer binds to the antioxidantresponse element (ARE) 2 or electrophile-response element located in the regulatory regions of many cytoprotective enzyme genes (1, 4 -6). In this way, Nrf2 activates a wide range of cellular defense processes, thereby eliminating harmful substances.Keap1 acts as an E3 ubiquitin ligase substrate-recognition subunit and specifically targets Nrf2 (7-10). In the absence of stress, Nrf2 is efficiently ubiquitinated by the Keap1-Cul3 E3 ligase and degraded rapidly through the proteasome pathway, such that cellular Nrf2 activity is constitutively suppressed. Upon exposure to oxidative or electrophilic stresses, Keap1 loses its ability to ubiquitinate Nrf2, allowing Nrf2 to accumulate in the nucleus and activate its target genes.Recent studies expanded our knowledge on the targets of the Keap1-Nrf2 system, and the molecular mechanisms underpinning how this system senses a variety of environmental stresses. Keap1 primarily regulates Nrf2 in the cytoplasm; however, a Keap1-independent mechanism utilizing ␤-TrCP (␤-transducin repeat-containing protein) in the nucleus also operates (11). Anti-inflammation by Nrf2Several hundred Nrf2 target genes have been identified through gene expression profiling analysis and chromatin immunoprecipitation (ChIP) analysis (12-17). The Nrf2 target genes identified in these studies include enzymes involved in detoxification, anti-oxidation, and metabolism, as summarized in Fig. 1 (18).In addition to protecting against oxidative and xenobiotic insults, Nrf2 has also been known to attenuate inflammation (19). Nrf2 deficiency exacerbates inflammation, such as sepsis, pleurisy, and emphysema, in a variety of murine models (20 -22). In human clinical studies, the Nrf2 inducer Tecfidera (dimethyl fumarate) has been approved for the treatment of multiple sclerosis (23, 24)-at least in part based on its antiinflammatory function. Thus, N...

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confidence: 73%

Section: Minireview: Stress Response By the Keap1-nrf2 Systemmentioning

confidence: 95%

Stress-sensing mechanisms and the physiological roles of the Keap1–Nrf2 system during cellular stress

Suzuki

Yamamoto

2017

Journal of Biological Chemistry

337

272

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“…29,30 We found that after incubation with resveratrol for 6 hours, NRF2 dissociated from Kelch-like ECH-associated protein 1 and translocated to the nucleus, where it became active ( Figure 4A). This was associated with overexpression of MnSOD ( Figure 3D).…”

Section: Resveratrol Activates Mnsod Through Nrf2mentioning

confidence: 98%

Resveratrol Improves Vascular Function in Patients With Hypertension and Dyslipidemia by Modulating NO Metabolism

et al. 2013

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Abstract-Epidemiological studies have demonstrated that the Mediterranean diet, which is rich in resveratrol, is associated with a significantly reduced risk of cardiovascular disease. However, the molecular mechanisms that underlie the beneficial effects of resveratrol on cardiovascular function remain incompletely understood. Therefore, we set out to identify the molecular target(s) mediating the protective action of resveratrol on vascular function. To this end, we performed vascular reactivity studies to evaluate the effects of resveratrol on superior thyroid artery obtained from 59 patients with hypertension and dyslipidemia. We found that resveratrol evoked vasorelaxation and reduced endothelial dysfunction through the modulation of NO metabolism via (1) an 5′ adenosine monophosphate-activated protein kinase-mediated increase in endothelial NO synthase activity; (2) a rise in tetrahydrobiopterin levels, which also increases endothelial NO synthase activity; and (3) attenuation of vascular oxidative stress, brought about by overexpression of manganese superoxide dismutase via an nuclear factor erythroid-derived 2-like 2-dependent mechanism. The effects of resveratrol on acetylcholine vasorelaxation were also tested in vessels from patients with nonhypertensive nondyslipidemia undergoing thyroid surgery. In this setting, resveratrol failed to exert any effect. Thus, our finding that resveratrol reduces endothelial dysfunction, an early pathophysiological feature and independent predictor of poor prognosis in most forms of cardiovascular disease, supports the concept that the risk of vascular events could be further reduced by adherence to a set of dietary and behavioral guidelines. MethodsFor detailed methodology, please see the online-only Data Supplement. In brief, we collected superior thyroid artery (STA) from patients with HD (Table). Each vessel was divided into rings for use in different experimental series. Some rings were treated with resveratrol at 37°C, and then proteins were rapidly extracted for molecular studies to evaluate total and phosphorylated endothelial NO synthase (eNOS) protein levels, eNOS dimerization, GTP cyclohydrolase 1, copper-zinc superoxide dismutase (Cu-ZnSOD) and MnSOD expression, and NRF2 translocation; other rings were kept in 4°C Krebs solution for vascular reactivity studies; some were used for highperformance liquid chromatography (HPLC) dosage of BH 4 ; and others were rapidly used for measurement of O 2 − . Studies were also performed on vessels removed from patients with nonhypertensive, nondyslipidemia (nHD) undergoing thyroid surgery. Results Resveratrol Exerts a Vasorelaxant Effect by Modulating the Phosphorylation Status of eNOS and NO ReleaseEvaluation of the vascular reactivity of ex vivo STA from patients with HD revealed that endothelially mediated (acetylcholine-evoked) vasorelaxation was significantly blunted compared with relaxation induced by nitroglycerin ( Figure 1A). However, when HD STA rings were preconstricted with phenylephrine, resveratrol was ca...

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“…In humans, enhanced Nrf2 expression is found in various types of epithelial cancer bearing mutations within the NRF2 gene (18) and also in oncogene-driven cancer tissue, where Nrf2 promotes antioxidant programs (19). SFN directly activates Nrf2 by binding cysteine residues of kelch-like ECH-associated protein 1 (Keap1), which is responsible for Nrf2 ubiquitination (20). SFN blocks the function of Keap1, resulting in Nrf2 stabilization.…”

mentioning

confidence: 99%

Sulforaphane Protects from T Cell–Mediated Autoimmune Disease by Inhibition of IL-23 and IL-12 in Dendritic Cells

Geisel

Brück

Glocova

et al. 2014

The Journal of Immunology

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Sulforaphane (SFN), an isothiocyanate, is part of an important group of naturally occurring small molecules with anti-inflammatory properties. The published reports are best conceivable with an inhibition of T cell function, but the mode of action remains unknown. We therefore analyzed the effect of SFN on T cell–mediated autoimmune disease. Feeding mice with SFN protected from severe experimental autoimmune encephalomyelitis. Disease amelioration was associated with reduced IL-17 and IFN-γ expression in draining lymph nodes. In vitro, SFN treatment of T cells did not directly alter T cell cytokine secretion. In contrast, SFN treatment of dendritic cells (DCs) inhibited TLR4-induced IL-12 and IL-23 production, and severely suppressed Th1 and Th17 development of T cells primed by SFN-treated DCs. SFN regulated the activity of the TLR4-induced transcription factor NF-κB, without affecting the degradation of its inhibitor IκB-α. Instead, SFN treatment of DCs resulted in strong expression of the stress response protein heme oxygenase-1 (HO-1), which interacts with and thereby inhibits NF-κB p65. Consistent with these findings, HO-1 bound to p65 and subsequently inhibited the p65 activity at the IL23a and IL12b promoters. Importantly, SFN suppressed Il23a and Il12b expression in vivo and silenced Th17/Th1 responses within the CNS. Thus, our data show that SFN improves Th17/Th1-mediated autoimmune disease by inducing HO-1 and inhibiting NF-κB p65-regulated IL-23 and IL-12 expression.

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Mechanism of Chemical Activation of Nrf2

Cited by 138 publications

References 42 publications

Stress-sensing mechanisms and the physiological roles of the Keap1–Nrf2 system during cellular stress

Stress-sensing mechanisms and the physiological roles of the Keap1–Nrf2 system during cellular stress

Resveratrol Improves Vascular Function in Patients With Hypertension and Dyslipidemia by Modulating NO Metabolism

Sulforaphane Protects from T Cell–Mediated Autoimmune Disease by Inhibition of IL-23 and IL-12 in Dendritic Cells

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