Multiple roles of Nrf2-Keap1 signaling

Huai, Dongxin

doi:10.4161/fly.27007

Cited by 28 publications

(11 citation statements)

References 51 publications

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“…Because mutations in other genes (e.g. Foxo and Nrf2) [48] , [49] that cause sensitivity to oxidative stress also affect sensitivity to other stressors, we also tested whether KDM5 knockdown adults were sensitive to treatment with a xenobiotic. Adult specific RNAi-mediated knockdown of KDM5 resulted in sensitivity to the well-characterized insecticide DDT (dichloro-diphenyl-trichloroethane) ( Figure S4F ).…”

Section: Resultsmentioning

confidence: 99%

KDM5 Interacts with Foxo to Modulate Cellular Levels of Oxidative Stress

2014

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Increased cellular levels of oxidative stress are implicated in a large number of human diseases. Here we describe the transcription co-factor KDM5 (also known as Lid) as a new critical regulator of cellular redox state. Moreover, this occurs through a novel KDM5 activity whereby it alters the ability of the transcription factor Foxo to bind to DNA. Our microarray analyses of kdm5 mutants revealed a striking enrichment for genes required to regulate cellular levels of oxidative stress. Consistent with this, loss of kdm5 results in increased sensitivity to treatment with oxidizers, elevated levels of oxidized proteins, and increased mutation load. KDM5 activates oxidative stress resistance genes by interacting with Foxo to facilitate its recruitment to KDM5-Foxo co-regulated genes. Significantly, this occurs independently of KDM5's well-characterized demethylase activity. Instead, KDM5 interacts with the lysine deacetylase HDAC4 to promote Foxo deacetylation, which affects Foxo DNA binding.

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Section: Resultsmentioning

confidence: 99%

KDM5 Interacts with Foxo to Modulate Cellular Levels of Oxidative Stress

2014

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“…CncC may also interact with Ras signaling pathway in metamorphosis and transcriptional regulation. Phosphorylation of CncC in response to Ras and possibly other signals can regulate the distribution of CncC on chromatin, resulting in the regulation of development and metamorphosis [ 59 , 60 ].…”

Section: Role Of Cnc Transcription Factors In Developmentmentioning

confidence: 99%

Role of Nrf2/HO-1 system in development, oxidative stress response and diseases: an evolutionarily conserved mechanism

Łoboda

Damulewicz

Pyza

et al. 2016

Cell. Mol. Life Sci.

1,959

1,313

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The multifunctional regulator nuclear factor erythroid 2-related factor (Nrf2) is considered not only as a cytoprotective factor regulating the expression of genes coding for anti-oxidant, anti-inflammatory and detoxifying proteins, but it is also a powerful modulator of species longevity. The vertebrate Nrf2 belongs to Cap ‘n’ Collar (Cnc) bZIP family of transcription factors and shares a high homology with SKN-1 from Caenorhabditis elegans or CncC found in Drosophila melanogaster. The major characteristics of Nrf2 are to some extent mimicked by Nrf2-dependent genes and their proteins including heme oxygenase-1 (HO-1), which besides removing toxic heme, produces biliverdin, iron ions and carbon monoxide. HO-1 and their products exert beneficial effects through the protection against oxidative injury, regulation of apoptosis, modulation of inflammation as well as contribution to angiogenesis. On the other hand, the disturbances in the proper HO-1 level are associated with the pathogenesis of some age-dependent disorders, including neurodegeneration, cancer or macular degeneration. This review summarizes our knowledge about Nrf2 and HO-1 across different phyla suggesting their conservative role as stress-protective and anti-aging factors.

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“…In D. melanogaster, this mechanism is analogous to the one reported in mammals. NRF2 in flies is referred to as CncC, and it is part of the transcription factor family Cap’n’collar [102, 103], which activates many cytochrome P450 and GST coding genes [103–105]. The gene CG3962 encodes a Kelch protein, which is similar to KEAP1 [103].…”

Section: Discussionmentioning

confidence: 99%

Simultaneous exposure to vinylcyclohexene and methylmercury in Drosophila melanogaster: biochemical and molecular analyses

Piccoli

Segatto

Oliveira

et al. 2019

BMC Pharmacol Toxicol

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BackgroundExposure to vinylcyclohexene (VCH) and methylmercury (MeHg+) can induce oxidative stress and gene modulation. Several studies have been evaluating the effects of VCH and MeHg+, but little is known about interactive effects between them. This work aimed to assess the exposure and co-exposure effects of MeHg+ and VCH on oxidative stress and gene modulation in Drosophila melanogaster.MethodsReactive species production, glutathione S-transferase (GST) and acetylcholinesterase (AChE) activities were evaluated after exposure and co-exposure to VCH (1 mM) and MeHg+ (0.2 mM) for one or three days in the head and body (thorax and abdomen) of flies. The expression of genes related to redox state and inflammatory response was evaluated after exposure and co-exposure to VCH and MeHg+ for three days.ResultsSurvival decreased only in flies co-exposed to VCH and MeHg+ for three days. All treatments increased total reactive species production after one day of exposure. However, no significant changes were observed in the head after three days of exposure. One day of exposure to VCH caused an increase in the head GST activity, whereas MeHg+ induced an increase after three days of exposure. Regarding the body, all treatments increased GST activity after one day of exposure, but only the flies exposed to MeHg+ presented an increase in GST activity after three days of exposure. Treatments did not alter AChE activity in the head. As for gene expression, there was a significant increase in the Relish transcription factor gene in the flies’ body, but Nrf2, Keap1, Jafrac1, TrxR1, and NF-κβ were not altered.ConclusionThe results suggest that exposure to VCH and MeHg+ induce oxidative stress and activation of an inflammatory response in fruit flies.

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Multiple roles of Nrf2-Keap1 signaling

Cited by 28 publications

References 51 publications

KDM5 Interacts with Foxo to Modulate Cellular Levels of Oxidative Stress

KDM5 Interacts with Foxo to Modulate Cellular Levels of Oxidative Stress

Role of Nrf2/HO-1 system in development, oxidative stress response and diseases: an evolutionarily conserved mechanism

Simultaneous exposure to vinylcyclohexene and methylmercury in Drosophila melanogaster: biochemical and molecular analyses

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