Keap1/Nrf2 Signaling Regulates Oxidative Stress Tolerance and Lifespan in Drosophila

Sykiotis, Gerasimos P.; Bohmann, Dirk

doi:10.1016/j.devcel.2007.12.002

Cited by 612 publications

(717 citation statements)

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“…Similarly, disruption of Nrf2 impairs the resolution of hyperoxia-induced acute lung injury and inflammation in mice (11). INrf2-Nrf2 signaling has also been shown to regulate oxidative stress tolerance and life span in Drosophila (12). Furthermore, Nrf2…”

mentioning

confidence: 99%

Src Subfamily Kinases Regulate Nuclear Export and Degradation of Transcription Factor Nrf2 to Switch Off Nrf2-mediated Antioxidant Activation of Cytoprotective Gene Expression

Niture

Jain

Shelton

et al. 2011

Journal of Biological Chemistry

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Nrf2 (NF-E2-related factor 2) is a nuclear transcription factor that in response to chemical and radiation stress regulates coordinated induction of a battery of cytoprotective gene expressions leading to cellular protection. In this study, we investigated the role of Src kinases in the regulation of Nrf2 and downstream signaling. siRNA-mediated inhibition of Fyn, Src, Yes, and Fgr, but not Lyn, in mouse hepatoma Hepa-1 cells, led to nuclear accumulation of Nrf2 and up-regulation of Nrf2 downstream gene expression. Mouse embryonic fibroblasts with combined deficiency of Fyn/Src/Yes/Fgr supported results from siRNA. In addition, steady-state overexpression of Fyn, Src, and Yes phosphorylated Nrf2Tyr568 that triggered nuclear export and degradation of Nrf2 and down-regulation of Nrf2 downstream gene expression. Exposure of cells to antioxidant, oxidant, or UV radiation increased nuclear import of Fyn, Src, and Yes kinases, which phosphorylated Nrf2Tyr568 resulting in nuclear export and degradation of Nrf2. Further analysis revealed that stress-activated GSK3␤ acted upstream to the Src kinases and phosphorylated the Src kinases, leading to their nuclear localization and Nrf2 phosphorylation. The overexpression of Src kinases in Hepa-1 cells led to decreased Nrf2, increased apoptosis, and decreased cell survival. Mouse embryonic fibroblasts deficient in Src kinases showed nuclear accumulation of Nrf2, induction of Nrf2 and downstream gene expression, reduced apoptosis, and increased cell survival. The studies together demonstrate that Src kinases play a critical role in nuclear export and degradation of Nrf2, thereby providing a negative feedback mechanism to switch off Nrf2 activation and restore normal cellular homeostasis.The INrf2⅐Nrf2 complex serves as a sensor of chemical-and radiation-induced oxidative and electrophilic stress (1, 2). Nrf2 resides predominantly in the cytoplasm where it interacts with actin-associated cytosolic protein, INrf2 (inhibitor of Nrf2) or Keap1 (Kelch-like ECH-associated protein 1). INrf2 functions as a substrate adaptor protein for a Cul3⅐Rbx1-dependent E3 ubiquitin ligase complex that ubiquitinates and degrades Nrf2, thus maintaining steady-state levels of Nrf2 (1, 2). Nrf2 is a nuclear transcription factor that coordinately activates expression of more than 200 cytoprotective genes required for protection of cells against stressors (1, 2). The mechanisms by which Nrf2 is released from INrf2 under stress have been actively investigated. One mechanism is that cysteine thiol groups of INrf2 function as sensors for oxidative stress, which are modified by the chemical inducers, causing formation of disulfide bonds between cysteines of two INrf2 peptides. This leads to a conformational change that renders INrf2 unable to bind with Nrf2 (3, 4). Another mechanism is that antioxidant-induced protein kinase C (PKC) phosphorylates Nrf2Ser-40, leading to dissociation of Nrf2 from INrf2 and nuclear localization of Nrf2 (5, 6). Recently, it has been shown that the two mechanisms work in concer...

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confidence: 99%

Src Subfamily Kinases Regulate Nuclear Export and Degradation of Transcription Factor Nrf2 to Switch Off Nrf2-mediated Antioxidant Activation of Cytoprotective Gene Expression

Niture

Jain

Shelton

et al. 2011

Journal of Biological Chemistry

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“…Alternatively, there may be sex differences in the mechanisms that control the Keap1‐Nrf2 pathway. For example, Sykiotis & Bohmann (2008) reported that D . melanogaster carrying a loss of function mutation in Keap1 had increased Nrf2 activity, increased oxidative stress resistance, and elevated longevity, but in male flies only.…”

Section: Discussionmentioning

confidence: 99%

Longer lifespan in male mice treated with a weakly estrogenic agonist, an antioxidant, an α‐glucosidase inhibitor or a Nrf2‐inducer

et al. 2016

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SummaryThe National Institute on Aging Interventions Testing Program (ITP) evaluates agents hypothesized to increase healthy lifespan in genetically heterogeneous mice. Each compound is tested in parallel at three sites, and all results are published. We report the effects of lifelong treatment of mice with four agents not previously tested: Protandim, fish oil, ursodeoxycholic acid (UDCA) and metformin – the latter with and without rapamycin, and two drugs previously examined: 17‐α‐estradiol and nordihydroguaiaretic acid (NDGA), at doses greater and less than used previously. 17‐α‐estradiol at a threefold higher dose robustly extended both median and maximal lifespan, but still only in males. The male‐specific extension of median lifespan by NDGA was replicated at the original dose, and using doses threefold lower and higher. The effects of NDGA were dose dependent and male specific but without an effect on maximal lifespan. Protandim, a mixture of botanical extracts that activate Nrf2, extended median lifespan in males only. Metformin alone, at a dose of 0.1% in the diet, did not significantly extend lifespan. Metformin (0.1%) combined with rapamycin (14 ppm) robustly extended lifespan, suggestive of an added benefit, based on historical comparison with earlier studies of rapamycin given alone. The α‐glucosidase inhibitor, acarbose, at a concentration previously tested (1000 ppm), significantly increased median longevity in males and 90th percentile lifespan in both sexes, even when treatment was started at 16 months. Neither fish oil nor UDCA extended lifespan. These results underscore the reproducibility of ITP longevity studies and illustrate the importance of identifying optimal doses in lifespan studies.

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“…54,55 The activation of Nrf2 signaling by a Keap1 loss-of-function mutation augments tolerance to oxidative stress and confers increased lifespan in Drosophila. 55 Nrf2-dependent signaling has been reported to restore the loss of proteostasis and prevent premature aging in Drosophila.…”

Section: Nrf2 In Agingmentioning

confidence: 99%

Nuclear Factor–Erythroid-2–Related Factor 2 in Aging and Lung Fibrosis

Swamy

Rajasekaran

Thannickal

2016

The American Journal of Pathology

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Aging and age-related diseases have been associated with elevated oxidative stress, which may be related to increased production of reactive species and/or a deficiency in antioxidant defenses. The nuclear factor-erythroid-2erelated factor 2 (Nrf2)-mediated antioxidant response pathway maintains cellular reduction-oxidation homeostasis by inducing the transcription of an array of cytoprotective genes. However, there is evidence of impaired Nrf2 response in aging contributing to age-related fibrotic diseases. Herein, we review mechanisms for the dysregulation of Nrf2 signaling in aging. This understanding will pave the way for the design of novel therapeutic strategies that restore Nrf2 signaling to reestablish cellular homeostasis in aging and age-related fibrotic diseases.

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Keap1/Nrf2 Signaling Regulates Oxidative Stress Tolerance and Lifespan in Drosophila

Cited by 612 publications

References 47 publications

Src Subfamily Kinases Regulate Nuclear Export and Degradation of Transcription Factor Nrf2 to Switch Off Nrf2-mediated Antioxidant Activation of Cytoprotective Gene Expression

Src Subfamily Kinases Regulate Nuclear Export and Degradation of Transcription Factor Nrf2 to Switch Off Nrf2-mediated Antioxidant Activation of Cytoprotective Gene Expression

Longer lifespan in male mice treated with a weakly estrogenic agonist, an antioxidant, an α‐glucosidase inhibitor or a Nrf2‐inducer

Nuclear Factor–Erythroid-2–Related Factor 2 in Aging and Lung Fibrosis

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