Mitogenic Signaling Mediated by Oxidants in Ras-Transformed Fibroblasts

Irani, Kaikobad; Xia, Yong; Zweíer, Jay L.; Sollott, Steven J.; Der, Channing J.; Fearon, Eric R.; Sundaresan, Maitrayee; Finkel, Toren; Goldschmidt‐Clermont, Pascal J.

doi:10.1126/science.275.5306.1649

Cited by 1,498 publications

(1,122 citation statements)

References 34 publications

(26 reference statements)

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“…19 To that effect, mitogenic signal triggered by the oncogene Ras in a fibroblast cell line was attributed to Rac-dependent intracellular production of O2 KÀ , thereby lending support to the hypothesis that O2 KÀ acts as an important proliferative signal during tumorigenesis. 22 Along similar lines, Reshkin et al 31 have recently demonstrated that just as efficient Ras-mediated transformation requires activation of Rac, NHE-1 protein expression was equally implicated in malignant transformation and the development of the transformed phenotype. 32 Taken together, these findings suggest that, in addition to activation of the exchanger leading to alkaline pHi, redox regulation of NHE-1 gene expression could be critical in tumor cell formation.…”

Section: Discussionmentioning

confidence: 94%

Reactive oxygen species-mediated regulation of the Na+–H+ exchanger 1 gene expression connects intracellular redox status with cells' sensitivity to death triggers

et al. 2005

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We have previously demonstrated that a slight increase in intracellular superoxide (O 2 KÀ ) anion confers resistance to death stimuli. Using pharmacological and molecular approaches to manipulate intracellular O 2 KÀ , here we report that an increase in intracellular O 2 KÀ anion induces Na þ /H þ exchanger 1 (NHE-1) gene promoter activity resulting in increased NHE-1 protein expression, which strongly correlates with the resistance of cells to death stimuli. In contrast, exposure to exogenous hydrogen peroxide suppressed NHE-1 promoter activity and gene expression, and increased cell sensitivity to death triggers. Furthermore, the increase in cell sensitivity to death upon downregulation of NHE-1 gene expression correlates with reduced capacity of cells to recover from an acid load, while survival upon overexpression of NHE-1 appears independent of its pump activity. These findings indicate that NHE-1 is a redox-regulated gene, and provide a novel intracellular target for the redox control of cell death sensitivity.

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Section: Discussionmentioning

confidence: 94%

Reactive oxygen species-mediated regulation of the Na+–H+ exchanger 1 gene expression connects intracellular redox status with cells' sensitivity to death triggers

et al. 2005

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“…Moreover, cells expressing the mutant ras (H-ras-V12) were shown to produce a large amount of ROS (Irani et al, 1997), resulting in the activation of MAPK, ERK, ELK1 and c-fos (Muller et al, 1997a,b). Molecular interactions between nitric oxide (NO) and p21 ras activates p21-mediated signaling.…”

Section: Ros-induced Dimerization Of Ask1mentioning

confidence: 99%

Role of redox potential and reactive oxygen species in stress signaling

et al. 1999

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Stress-activated signaling cascades are a ected by altered redox potential. Key contributors to altered redox potential are reactive oxygen species (ROS) which are formed, in most cases, by exogenous genotoxic agents including irradiation, in¯ammatory cytokines and chemical carcinogens. ROS and altered redox potential can be considered as the primary intracellular changes which regulate protein kinases, thereby serving as an important cellular component linking external stimuli with signal transduction in stress response. The mechanisms, which underlie the ROS-mediated response, involve direct alteration of kinases and transcription factors, and indirect modulation of cysteine-rich redox-sensitive proteins exempli®ed by thioredoxin and glutathione Stransferase. This review summarizes the current understanding of the mechanisms contributing to ROS-related changes in key stress activated signaling cascades.

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“…The senescence response to the RAS oncoprotein has been ascribed to its production of reactive oxygen species (ROS) (Irani et al, 1997;Lee et al, 1999) and to the resulting induction of a DNA damage response (DDR) (Di Micco et al, 2006;Mallette et al, 2007). However, the connection between these two RAS-induced effects has been unclear.…”

Section: Introductionmentioning

confidence: 99%

Enhanced elimination of oxidized guanine nucleotides inhibits oncogenic RAS-induced DNA damage and premature senescence

et al. 2010

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Approximately 20% of tumors contain activating mutations in the RAS family of oncogenes. As tumors progress to higher grades of malignancy, the expression of oncogenic RAS has been reported to increase, leading to an oncogene-induced senescence (OIS) response. Evasion of this senescence barrier is a hallmark of advanced tumors indicating that OIS serves a critical tumorsuppressive function. Induction of OIS has been attributed to either RAS-mediated production of reactive oxygen species (ROS) or to induction of a DNA damage response (DDR). However, functional links between these two processes in triggering the senescent phenotype have not been explicitly described. Our previous work has shown that, in cultured untransformed cells, preventing elimination of oxidized guanine deoxyribonucleotides, which was achieved by suppressing expression of the cellular 8-oxodGTPase, human MutT homolog 1 (MTH1), sufficed to induce a DDR as well as premature senescence. Here, we demonstrate that overexpression of MTH1 can prevent the oncogenic H-RAS-induced DDR and attendant premature senescence, although it does not affect the observed elevation in ROS levels produced by RAS oncoprotein expression. Conversely, we find that loss of MTH1 preferentially induces an in vitro proliferation defect in tumorigenic cells overexpressing oncogenic RAS. These results indicate that the guanine nucleotide pool is a critical target for intracellular ROS produced by oncogenic RAS and that RAS-transformed cells require robust MTH1 expression to proliferate.

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Mitogenic Signaling Mediated by Oxidants in Ras-Transformed Fibroblasts

Cited by 1,498 publications

References 34 publications

Reactive oxygen species-mediated regulation of the Na+–H+ exchanger 1 gene expression connects intracellular redox status with cells' sensitivity to death triggers

Reactive oxygen species-mediated regulation of the Na+–H+ exchanger 1 gene expression connects intracellular redox status with cells' sensitivity to death triggers

Role of redox potential and reactive oxygen species in stress signaling

Enhanced elimination of oxidized guanine nucleotides inhibits oncogenic RAS-induced DNA damage and premature senescence

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