Nrf2 regulates the sensitivity of death receptor signals by affecting intracellular glutathione levels

Morito, Naoki; Yoh, Keigyou; Itoh, Ken; Hirayama, Aki; Kôyama, Akio; Yamamoto, Masayuki; Takahashi, Satoru

doi:10.1038/sj.onc.1207024

Cited by 103 publications

(73 citation statements)

References 42 publications

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“…They also found that overexpression of Nrf2 protects cells from Fas-induced apoptosis suggesting an important role of Nrf2 in anti-apoptotic pathways (Kotlo et al, 2003). Furthermore, Nrf2 is an important effector of PERKmediated cell survival (Cullinan et al, 2003), and Nrf2 regulates the sensitivity of death receptor signals (Morito et al, 2003). Collectively, these observations suggest that Nrf2-ARE pathway play an important role in cellular survival by modulating both cellular antioxidant potential and apoptosis pathway.…”

Section: Nrf2 Confers Cytoprotectionmentioning

confidence: 70%

An Important Role of Nrf2-ARE Pathway in the Cellular Defense Mechanism

Lee¹,

Johnson²

2004

BMB Reports

553

456

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The antioxidant responsive element (ARE) is a cis-acting regulatory element of genes encoding phase II detoxification enzymes and antioxidant proteins, such as NAD(P)H: quinone oxidoreductase 1, glutathione S-transferases, and glutamate-cysteine ligase. Interestingly, it has been reported that Nrf2 (NF-E2-related factor 2) regulates a wide array of ARE-driven genes in various cell types. Nrf2 is a basic leucine zipper transcription factor, which was originally identified as a binding protein of locus control region of ß-globin gene. The DNA binding sequence of Nrf2 and ARE sequence are very similar, and many studies demonstrated that Nrf2 binds to the ARE sites leading to up-regulation of downstream genes. The function of Nrf2 and its downstream target genes suggests that the Nrf2-ARE pathway is important in the cellular antioxidant defense system. In support of this, many studies showed a critical role of Nrf2 in cellular protection and anti-carcinogenicity, implying that the Nrf2-ARE pathway may serve as a therapeutic target for neurodegenerative diseases and cancers, in which oxidative stress is closely implicated.

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Section: Nrf2 Confers Cytoprotectionmentioning

confidence: 70%

An Important Role of Nrf2-ARE Pathway in the Cellular Defense Mechanism

Lee¹,

Johnson²

2004

BMB Reports

553

456

View full text Add to dashboard Cite

show abstract

“…One study actually implies that Nrf2 is a substrate for caspase-3-like proteases (15), and another indicates that Nrf2 inhibits Fas-mediated apoptosis pathway (16). Moreover, Nrf2 is an important effector of PERK-mediated cell survival (17) and regulates the sensitivity of death receptor signals (18). These data suggest that the Nrf2-ARE pathway promotes cell survival by modulating both cellular antioxidant potentials and apoptosis signaling pathways.…”

mentioning

confidence: 89%

Targeted disruption of Nrf2 causes regenerative immune-mediated hemolytic anemia

Lee

Chan

Kan

et al. 2004

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

113

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A basic leucine zipper transcription factor, NF-E2-related factor 2 (Nrf2), plays a critical role in the cellular defense mechanism by mediating a coordinate up-regulation of antioxidant responsive element-driven detoxification and antioxidant genes. Here, we report that targeted disruption of Nrf2 causes regenerative immune-mediated hemolytic anemia due to increased sequestration of damaged erythrocytes. Splenomegaly and spleen toxicity in Nrf2 ؊/؊ mice raised a possibility of hemolytic anemia and splenic extramedullary hematopoiesis in Nrf2 ؊/؊ mice. In support of this, hematology analysis revealed that Nrf2 ؊/؊ mice suffer from anemia with abnormal red cell morphologies (i.e., Howell-Jolly bodies, acantocytes, and schistocytes). In addition, Nrf2 ؊/؊ erythrocytes were more sensitive to H 2O2-induced hemolysis, and erythrocytebound IgG levels were markedly increased in Nrf2 ؊/؊ mice compared with Nrf2 ؉/؉ mice. Because IgG bound to erythrocytes in the presence of oxidative damage in erythrocytes (regardless of Nrf2 genotype), these data support that Nrf2 ؊/؊ erythrocytes have higher levels of damage compared with Nrf2 ؉/؉ cells. Finally, Nrf2 ؊/؊ mice showed increased levels of erythrocyte-bound IgG compared with Nrf2 ؉/؉ mice after H2O2 injection in vivo, suggesting that the decreased glutathione and increased H 2O2 render the Nrf2 ؊/؊ mice more susceptible to toxicity. Taken together, these observations indicate that a chronic increase in oxidative stress due to decreased antioxidant capacity sensitizes erythrocytes and causes hemolytic anemia in Nrf2 ؊/؊ mice, suggesting a pivotal role of Nrf2-antioxidant responsive element pathway in the cellular antioxidant defense system.

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“…Nrf2 has the ability to reduce the ROS and DNA damage in chemical-induced carcinogen cells (Morito et al 2003). Other studies showed the protective role of Nrf2 in mice, harbouring a single nucleotide polymorphism (SNP) in the promoter region of the mouse Nrf2 gene.…”

Section: Role Of the Nrf2-keap1 Pathway In Cancermentioning

confidence: 99%

The Keap1–Nrf2 pathway: promising therapeutic target to counteract ROS-mediated damage in cancers and neurodegenerative diseases

et al. 2016

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The overproduction of reactive oxygen species (ROS) generates oxidative stress in cells. Oxidative stress results in various pathophysiological conditions, especially cancers and neurodegenerative diseases (NDD). The Keap1-Nrf2 [Kelch-like ECH-associated protein 1-nuclear factor (erythroid-derived 2)-like 2] regulatory pathway plays a central role in protecting cells against oxidative and xenobiotic stresses. The Nrf2 transcription factor activates the transcription of several cytoprotective genes that have been implicated in protection from cancer and NDD. The Keap1-Nrf2 system acts as a double-edged sword: Nrf2 activity protects cells and makes the cell resistant to oxidative and electrophilic stresses, whereas elevated Nrf2 activity helps in cancer cell survival and proliferation. Several groups in the recent past, from both academics and industry, have reported the potential role of Nrf2-mediated transcription to protect from cancer and NDD, resulting from mechanisms involving xenobiotic and oxidative stress. It suggests that the Keap1-Nrf2 system is a potential therapeutic target to combat cancer and NDD by designing and developing modulators (inhibitors/activators) for Nrf2 activation. Herein, we review and discuss the recent advancement in the regulation of the Keap1-Nrf2 system, its role under physiological and pathophysiological conditions including cancer and NDD, and modulators design strategies for Nrf2 activation.

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Nrf2 regulates the sensitivity of death receptor signals by affecting intracellular glutathione levels

Cited by 103 publications

References 42 publications

An Important Role of Nrf2-ARE Pathway in the Cellular Defense Mechanism

An Important Role of Nrf2-ARE Pathway in the Cellular Defense Mechanism

Targeted disruption of Nrf2 causes regenerative immune-mediated hemolytic anemia

The Keap1–Nrf2 pathway: promising therapeutic target to counteract ROS-mediated damage in cancers and neurodegenerative diseases

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