Keap1: One stone kills three birds Nrf2, IKKβ and Bcl-2/Bcl-xL

Tian, Hui; Zhang, Baofu; Di, Jiehui; Jiang, Guan; Chen, FeiFei; Li, Huizhong; Li, Liantao; Pei, Dong‐Sheng; Zheng, Junnian

doi:10.1016/j.canlet.2012.06.007

Cited by 93 publications

(67 citation statements)

References 89 publications

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“…Although Nrf2 is the best characterized and primary Keap1 substrate, other Keap1 substrates or interacting proteins have been found, at least including IKKβ, Bcl-2/Bcl-xL, p62/sequestosome-1, and p21. 41 Thus, it warrants future studies to elucidate how Keap1 exerts regulatory effects in addition to Nrf2-mediated pathway during liver regeneration. Moreover, we observed that, in Keap1+/− regenerating livers, Nrf2 target genes were upregulated at later stage during the first round of hepatocyte cell cycle, although Keap1 protein levels were reduced throughout this period (Fig.…”

Section: Discussionmentioning

confidence: 99%

Keap1 modulates the redox cycle and hepatocyte cell cycle in regenerating liver

Zou

Nambiar

et al. 2014

Cell Cycle

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Section: Discussionmentioning

confidence: 99%

Keap1 modulates the redox cycle and hepatocyte cell cycle in regenerating liver

Zou

Nambiar

et al. 2014

Cell Cycle

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“…Under normal conditions, Nrf2 is predominantly present in the cytoplasm, bound in complex with Kelch-like ECH-associated protein1 (Keap1). When oxidative stress disrupts the Keap1-Nrf2 complex, the dissociated Nrf2 enters the nucleus, subsequently binds to the antioxidant response elements (ARE) of the phase II genes, and accelerates transcription as a defense mechanism against oxidative stress [23] . Nrf2-regulated gene products include phase II detoxification enzymes, in addition to a range of regulators, including the enzymes NAD(P)H quinone oxidase 1 (NQO1) and heme oxygenase-1 (HO-1) [24,25] .…”

Section: Introductionmentioning

confidence: 99%

Protopanaxtriol protects against 3-nitropropionic acid-induced oxidative stress in a rat model of Huntington's disease

Gao

Chu

et al. 2015

Acta Pharmacol Sin

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Aim: Protopanaxtriol (Ppt) is extracted from Panax ginseng Mayer. In the present study, we investigated whether Ppt could protect against 3-nitropropionic acid (3-NP)-induced oxidative stress in a rat model of Huntington's disease (HD) and explored the mechanisms of action. Methods: Male SD rats were treated with 3-NP (20 mg/kg on d 1, and 15 mg/kg on d 2-5, ip). The rats received Ppt (5, 10, and 20 mg/kg, po) daily prior to 3-NP administration. Nimodipine (12 mg/kg, po) or N-acetyl cysteine (NAC, 100 mg/kg, po) was used as positive control drugs. The body weight and behavior were monitored within 5 d. Then the animals were sacrificed, neuronal damage in striatum was estimated using Nissl staining. Hsp70 expression was detected with immunohistochemistry. Reactive oxygen species (ROS) generation was measured using dihydroethidium (DHE) staining. The levels of components in the Nrf2 pathway were measured with immunohistochemistry and Western blotting. Results: 3-NP resulted in a marked reduction in the body weight and locomotion activity accompanied by progressive striatal dysfunction. In striatum, 3-NP caused ROS generation mainly in neurons rather than in astrocytes and induced Hsp70 expression. Administration of Ppt significantly alleviated 3-NP-induced changes of body weight and behavior, decreased ROS production and restored antioxidant enzymes activities in striatum. Moreover, Ppt directly scavenged free radicals, increased Nrf2 entering nucleus, and the expression of its downstream products heme oxygenase-1 (HO-1) and NAD(P)H quinone oxidase 1 (NQO1) in striatum. Similar effects were obtained with the positive control drugs nimodipine or NAC. Conclusion: Ppt exerts a protective action against 3-NP-induced oxidative stress in the rat model of HD, which is associated with its anti-oxidant activity.

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“…9 Under oxidative stress, Ikkβ is released from Keap1, and mediates the activation of Nf-kB regulated genes, resulting in increased growth, proliferation and anti-apoptosis, thus contributing to cell survival and tumor progression. 10 Moreover, recent studies suggest that under oxidative stress conditions Keap1 modulates the intrinsic apoptotic pathway through the degradation of Bcl2 and Bcl-xL antiapoptotic proteins. While Keap1 directly binds Bcl2, the effect on Bcl-xL is mediated by the interaction with Pgam5 protein, which acts as a bridge between Keap1 and Bcl-xL.…”

Section: Introductionmentioning

confidence: 99%