System xc− and Thioredoxin Reductase 1 Cooperatively Rescue Glutathione Deficiency

Mandal, Pankaj Kumar; Seiler, Alexander; Perisic, Tamara; Kölle, Petra; Canak, Ana Banjac; Förster, Heidi; Weiss, Norbert; Kremmer, Elisabeth; Lieberman, Michael W.; Bannai, Shiro; Kuhlencordt, Peter; Sato, Hiroki; Bornkamm, Georg W.; Conrad, Marcus

doi:10.1074/jbc.m110.121327

Cited by 198 publications

(154 citation statements)

References 45 publications

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“…This may be relevant to the pathogenesis of MS, as we have previously demonstrated in CSF and plasma of MS patients a significant decrease of GSH/GSSG ratio [5,9]. Consistent with this notion, it is well established that cellular redox regulation of many processes is provided by the cooperation between the Trx and glutathione systems [60]. In fact, Trx and GSH systems are involved in a variety of redox-dependent reactions, such as supplying reducing equivalents for ribonucleotide reductase, and peptide methionine sulfoxide reductase, the latter being involved in antioxidant defense and regulation of the cellular redox state [59].…”

Section: Discussionsupporting

confidence: 66%

Redox regulation of cellular stress response in multiple sclerosis

Pennisi

Cornelius

Cavallaro

et al. 2011

Biochemical Pharmacology

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Multiple sclerosis (MS) is an autoimmune-mediated neurodegenerative disease with characteristic foci of inflammatory demyelination in the brain, spinal cord, and optic nerves. Recent studies have demonstrated not only that axonal damage and neuronal loss are significant pathologic components of MS, but that this neuronal damage is thought to cause the permanent neurologic disability often seen in MS patients. Emerging finding suggests that altered redox homeostasis and increased oxidative stress, primarily implicated in the pathogenesis of MS, are a trigger for activation of a brain stress response. Relevant to maintenance of redox homeostasis, integrated mechanisms controlled by vitagenes operate in brain in preserving neuronal survival during stressful conditions. Vitagenes encode for heat shock proteins (Hsp) Hsp32, Hsp70, the thioredoxin and the sirtuin protein systems. In the present study we assess stress response mechanisms in the CSF, plasma and lymphocytes of control patients compared to MS patients. We found that the levels of vitagenes Hsp72, Hsc70, HO-1, as well as oxidative stress markers carbonyls and hydroxynonenals were significantly higher in the blood and CSF of MS patients than in control patients. In addition, an increased expression of Trx and sirtuin 1, together with a decrease in the expression of TrxR were observed. Our data strongly support a pivotal role for redox homeostasis disruption in the pathogenesis of MS and, consistently with the notion that new therapies that prevent neurodegeneration through nonimmunomodulatory mechanisms can have a tremendous potential to work synergistically with current MS therapies, unravel important targets for new cytoprotective strategies

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Section: Discussionsupporting

confidence: 66%

Redox regulation of cellular stress response in multiple sclerosis

Pennisi

Cornelius

Cavallaro

et al. 2011

Biochemical Pharmacology

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“…Recently, we showed that the cystine/cysteine cycle along with Txnrd1 cooperatively rescue GSH deficiency (35). Our data thus rule out a previously alleged indispensable role of Txnrd1 in cancer development.…”

Section: Discussionmentioning

confidence: 47%

“…Simultaneous inhibition of more than one antioxidant system for cancer therapy becomes even more important with the growing evidence that the two key redox systems display widespread redundant functions (35,50). Recently, we showed that the cystine/cysteine cycle along with Txnrd1 cooperatively rescue GSH deficiency (35).…”

Section: Discussionmentioning

confidence: 99%

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Loss of Thioredoxin Reductase 1 Renders Tumors Highly Susceptible to Pharmacologic Glutathione Deprivation

et al. 2010

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Tumor cells generate substantial amounts of reactive oxygen species (ROS), engendering the need to maintain high levels of antioxidants such as thioredoxin (Trx)-and glutathione (GSH)-dependent enzymes. Exacerbating oxidative stress by specifically inhibiting these types of ROS-scavenging enzymes has emerged as a promising chemotherapeutic strategy to kill tumor cells. However, potential redundancies among the various antioxidant systems may constrain this simple approach. Trx1 and thioredoxin reductase 1 (Txnrd1) are upregulated in numerous cancers, and Txnrd1 has been reported to be indispensable for tumorigenesis. However, we report here that genetic ablation of Txnrd1 has no apparent effect on tumor cell behavior based on similar proliferative, clonogenic, and tumorigenic potential. This finding reflects widespread redundancies between the Trx-and GSH-dependent systems based on evidence of a bypass to Txnrd1 deficiency by compensatory upregulation of GSH-metabolizing enzymes. Because the survival and growth of Txnrd1-deficient tumors were strictly dependent on a functional GSH system, Txnrd1 −/− tumors were highly susceptible to experimental GSH depletion in vitro and in vivo. Thus, our findings establish for the first time that a concomitant inhibition of the two major antioxidant systems is highly effective in killing tumor, highlighting a promising strategy to combat cancer. Cancer Res; 70(22); 9505-14. ©2010 AACR.

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“…To analyze the importance of the cytosolic Trx system for regulation of PTP oxidation, the oxidation states of PTP1B and SHP2 were monitored in mouse embryonic fibroblasts (MEFs) with WT or Txnrd1 knockout (Txnrd1 −/− ) genotypes (43).…”

Section: Oxidation Of Ptp1b But Not Shp2 Is Increased Inmentioning

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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System xc− and Thioredoxin Reductase 1 Cooperatively Rescue Glutathione Deficiency

Cited by 198 publications

References 45 publications

Redox regulation of cellular stress response in multiple sclerosis

Redox regulation of cellular stress response in multiple sclerosis

Loss of Thioredoxin Reductase 1 Renders Tumors Highly Susceptible to Pharmacologic Glutathione Deprivation

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

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