Cytoprotective Nrf2 Pathway Is Induced In Chronically Txnrd 1-Deficient Hepatocytes

Suvorova, Elena S.; Lucas, Olivier; Weisend, Carla; Rollins, Mary Clare F; Merrill, Gary F.; Capecchi, Mario R.; Schmidt, Edward E.

doi:10.1371/journal.pone.0006158

Cited by 88 publications

(151 citation statements)

References 60 publications

(96 reference statements)

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“…Thus, TrxR1 appears to counteract Nrf2 activation and/or serves as a turn-off signal for Nrf2 activation. However, TrxR1-deficient livers did not show evidence of oxidative stress, leaving the underlying mechanism unclear [51].…”

Section: Discussionmentioning

confidence: 98%

“…Since the thioredoxin reductase family belongs to the housekeeping selenoproteins [10], a liver-specific TrxR1 knockout was analyzed for potential activation of the Nrf2 pathway. Indeed, the TrxR1 knockout resulted in both, the nuclear accumulation of Nrf2 and the induction of 21 Nrf2 target genes [51]. mRNA levels of TrxR2, TrxR3 or thioredoxin were unaffected.…”

Section: Discussionmentioning

confidence: 98%

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Nrf2 target genes are induced under marginal selenium-deficiency

et al. 2010

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A suboptimal selenium supply appears to prevail in Europe. The current study, therefore, was focused on the changes in gene expression under a suboptimal selenium intake. Previous microarray analyses in the colon of mice fed either a selenium-adequate or a moderately deficient diet revealed a change in genes of several pathways. Severe selenium-deficiency has been found previously to influence Nrf2-regulated genes of the adaptive response. Since the previous pathway analyses were done with a program not searching for Nrf2 target genes, respective genes were manually selected and confirmed by qPCR. qPCR revealed an induction of phase II (Nqo1, Gsts, Sult1b1 and Ugt1a6) and antioxidant enzymes (Hmox1, Mt2, Prdx1, Srxn1, Sod1 and Gclc) under the selenium-poor diet, which is considered to compensate for the loss of selenoproteins. The strongest effects were observed in the duodenum where preferentially genes for antioxidant enzymes were up-regulated. These also include the mRNA of the selenoproteins TrxR1 and GPx2 that would enable their immediate translation upon selenium refeeding. The down-regulation of Gsk3b in moderate selenium-deficiency observed in the previous paper provides a possible explanation for the activation of the Nrf2 pathway, because inhibition of GSK3b results in the nuclear accumulation of Nrf2.

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Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 98%

Nrf2 target genes are induced under marginal selenium-deficiency

et al. 2010

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“…ROS-induced hormesis (54) could occur, whereby changes in other antioxidant genes could be evoked by acute redox stress after single gene knockdown. For example, knockout of TXNRD1 in hepatocytes leads to activation of Nrf2-mediated antioxidant gene transcription (55). Chronic adaptive remodeling is highly likely in cells or organisms with stable gene knockout and is a major complicating factor in the interpretation of results.…”

Section: Discussionmentioning

confidence: 99%

Compartment-specific Control of Reactive Oxygen Species Scavenging by Antioxidant Pathway Enzymes

Dey

Sidor

O’Rourke

2016

Journal of Biological Chemistry

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Oxidative stress arises from an imbalance in the production and scavenging rates of reactive oxygen species (ROS) and is a key factor in the pathophysiology of cardiovascular disease and aging. The presence of parallel pathways and multiple intracellular compartments, each having its own ROS sources and antioxidant enzymes, complicates the determination of the most important regulatory nodes of the redox network. Here we quantified ROS dynamics within specific intracellular compartments in the cytosol and mitochondria and determined which scavenging enzymes exert the most control over antioxidant fluxes in H9c2 cardiac myoblasts. We used novel targeted viral gene transfer vectors expressing redox-sensitive GFP fused to sensor domains to measure H 2 O 2 or oxidized glutathione. Using genetic manipulation in heart-derived H9c2 cells, we explored the contribution of specific antioxidant enzymes to ROS scavenging and glutathione redox potential within each intracellular compartment. Our findings reveal that antioxidant flux is strongly dependent on mitochondrial substrate catabolism, with availability of NADPH as a major rate-controlling step. Moreover, ROS scavenging by mitochondria significantly contributes to cytoplasmic ROS handling. The findings provide fundamental information about the control of ROS scavenging by the redox network and suggest novel interventions for circumventing oxidative stress in cardiac cells. Reactive oxygen species (ROS)2 serve as both signaling molecules and destructive agents, requiring cells to finely regulate their levels. Antioxidant enzymes catalyze ROS conversion directly via an active-site metal ion (e.g. superoxide dismutase or catalase) or through pathways involving the donation of an electron from the moiety-conserved redox couples thioredoxin and glutathione, which require continuous regeneration of the reduced species. Uncontrolled or uncontained ROS accumulation can affect numerous cell functions, including gene/protein expression, calcium handling, myofilament activation, bioenergetics, and substrate metabolism (1-4). Different ROS-generating and scavenging systems are present in distinct cellular compartments, and these may interact in complex ways that have not been well characterized.In cardiac myocytes, ROS are a byproduct of mitochondrial electron transport (5) and are also produced by extramitochondrial sources, including NADPH oxidase (1), uncoupled nitric oxide synthase (6), xanthine oxidase (7), and monoamine oxidase (8, 9). Both mitochondrial and extramitochondrial sources have been implicated in cardiac disorders including heart failure, myocardial ischemia, and arrhythmias. The dynamics and steady-state levels of ROS in local intracellular domains are determined by the rates of free radical generation and scavenging. Failure to scavenge free radicals via antioxidant fluxes can trigger a vicious cycle of dysfunction, leading to death (10). Recent studies have demonstrated that antioxidant enzymes targeted to the mitochondria, but not the cytoplasm, protect agai...

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“…Whole-body knockout mouse models for either TrxR1 or Trx1 are embryonically lethal (50,51). It is interesting to note that liver-specific knockouts for both Ptpn1 and Txnrd1 have been made (52)(53)(54). It will be an interesting topic for future studies to investigate similarities and differences of these mice related to receptordependent signaling pathways. )…”

Section: Discussionmentioning

confidence: 99%

“…It remains to obtain a complete picture of how conditional Trx1, or TRP14, deletion affects the oxidation state of the whole "PTPome" in different cell types, and downstream effects on signaling events. One interesting finding to further explore is the fact that TrxR1 knockout mice display early embryonic lethality (50,51), although the enzyme is dispensable in several conditional knockouts (52)(53)(54). Future studies should investigate whether this is related to aberrant signaling pathways related to inactivation of specific PTPs.…”

Section: Discussionmentioning

confidence: 99%

Selective activation of oxidized PTP1B by the thioredoxin system modulates PDGF-β receptor tyrosine kinase signaling

Dagnell

Frijhoff

Pader

et al. 2013

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

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The inhibitory reversible oxidation of protein tyrosine phosphatases (PTPs) is an important regulatory mechanism in growth factor signaling. Studies on PTP oxidation have focused on pathways that increase or decrease reactive oxygen species levels and thereby affect PTP oxidation. The processes involved in reactivation of oxidized PTPs remain largely unknown. Here the role of the thioredoxin (Trx) system in reactivation of oxidized PTPs was analyzed using a combination of in vitro and cell-based assays. Cells lacking the major Trx reductase TrxR1 (Txnrd1 −/− ) displayed increased oxidation of PTP1B, whereas SHP2 oxidation was unchanged. Furthermore, in vivo-oxidized PTP1B was reduced by exogenously added Trx system components, whereas SHP2 oxidation remained unchanged. Trx1 reduced oxidized PTP1B in vitro but failed to reactivate oxidized SHP2. Interestingly, the alternative TrxR1 substrate TRP14 also reactivated oxidized PTP1B, but not SHP2. Txnrd1-depleted cells displayed increased phosphorylation of PDGF-β receptor, and an enhanced mitogenic response, after PDGF-BB stimulation. The TrxR inhibitor auranofin also increased PDGF-β receptor phosphorylation. This effect was not observed in cells specifically lacking PTP1B. Together these results demonstrate that the Trx system, including both Trx1 and TRP14, impacts differentially on the oxidation of individual PTPs, with a preference of PTP1B over SHP2 activation. The studies demonstrate a previously unrecognized pathway for selective redox-regulated control of receptor tyrosine kinase signaling.redox regulation | cell signaling

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Cytoprotective Nrf2 Pathway Is Induced In Chronically Txnrd 1-Deficient Hepatocytes

Cited by 88 publications

References 60 publications

Nrf2 target genes are induced under marginal selenium-deficiency

Nrf2 target genes are induced under marginal selenium-deficiency

Compartment-specific Control of Reactive Oxygen Species Scavenging by Antioxidant Pathway Enzymes

Selective activation of oxidized PTP1B by the thioredoxin system modulates PDGF-β receptor tyrosine kinase signaling

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