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Cited by 1,588Protein Kinase Regulation and GTPase SignalingRedox biology and oxidative stressProtein Tyrosine Phosphatases

Mitogenic Signaling Mediated by Oxidants in Ras-Transformed Fibroblasts

Irani, Kaikobad, Xia, Yong, Zweier, Jay L., Sollott, Steven J., Der, Channing J., Fearon, Eric R., Sundaresan, Maitrayee, Finkel, Toren +1 more·1997·Science
DOI 10.1126/science.275.5306.1649
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Abstract

NIH 3T3 fibroblasts stably transformed with a constitutively active isoform of p21 Ras , H-Ras V12 (v-H-Ras or EJ-Ras), produced large amounts of the reactive oxygen species superoxide (·O 2 − ). ·O 2 − production was suppressed by the expression of dominant negative isoforms of Ras or Rac1, as well as by treatment with a farnesyltransferase inhibitor or with diphenylene iodonium, a flavoprotein inhibitor. The mitogenic activity of cells expressing H-Ras V12 was inhibited by treatment with the chemical antioxidant N -acetyl-L-cysteine. Mitogen-activated protein kinase (MAPK) activity was decreased and c-Jun N-terminal kinase (JNK) was not activated in H-Ras V12 -transformed cells. Thus, H-Ras V12 -induced transformation can lead to the production of ·O 2 − through one or more pathways involving a flavoprotein and Rac1. The implication of a reactive oxygen species, probably ·O 2 − , as a mediator of Ras-induced cell cycle progression independent of MAPK and JNK suggests a possible mechanism for the effects of antioxidants against Ras-induced cellular transformation.

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Crossref · 10.1126/science.275.5306.1649

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1 of 1 references verified0 citation errors · 0 not checkable

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  • Established oncogenes K-RAS and c-MYC induce intracellular ROS and have been shown to stabilize Nrf2.

    “Moreover, established oncogenes such as K-RAS and c-MYC, which had been previously demonstrated to induce intracellular ROS56,57, have been recently shown to stabilize Nrf258.”

    From ROS in cancer therapy: the bright side of the moon (2020) · cites this paper as [56]

  • The RAS mitogenic pathway signals through reactive oxygen species, generation of which is required for both the pathway's mitogenic effects and its ability to induce cellular senescence.

    “The RAS mitogenic pathway signals through reactive oxygen species (ROS), generation of which is required for both the pathway’s mitogenic effects (Irani et al., 1997) and ability to induce cellular senescence (Lee et al., 1999).”

    From Senescent cells, tumor suppression, and organismal aging: good citizens, bad neighbors (2005) · cites this paper as Irani et al., 1997

  • In these cells, the high levels of reactive oxygen species produced by RAS may trigger senescence by the p53 pathway.

    “In these cells, the high levels of ROS produced by RAS (Irani et al., 1997) may trigger senescence by the p53 pathway.”

    From Senescent cells, tumor suppression, and organismal aging: good citizens, bad neighbors (2005) · cites this paper as Irani et al., 1997

  • Elevation of reactive metabolites can support oncogenesis in some contexts.

    “While elevation of reactive metabolites can support oncogenesis in some contexts (Arnold et al., 2001; Irani et al., 1997; Suh et al., 1999; Weinberg et al., 2010), at high levels reactive metabolites become toxic and kill cells due to the resulting damage to the proteome and genome (Karisch et al., 2011; Rabbani and Thornalley, 2014).”

    From Targeting Metabolism for Cancer Therapy (2017) · cites this paper as Irani et al., 1997

  • Stimulants of mitosis and activated oncogenes like ras-Val12 generate reactive oxygen species believed to be functionally important in downstream signaling.

    “Mitogenic stimulants and activated oncogenes, such as ras-Val12, produce reactive oxygen species that are thought to be functionally important for the downstream signaling mechanisms (46,47).”

    From Glycolytic Enzymes Can Modulate Cellular Life Span (2005) · cites this paper as [47]

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Authors
Irani, K., Xia, Y., Zweier, J. L., Sollott, S. J., Der, C. J., Fearon, E. R., Sundaresan, M., Finkel, T., & Goldschmidt-Clermont, P. J.
Affiliations
  • Johns Hopkins University (US)
  • University of North Carolina at Chapel Hill (US)
  • University of Michigan (US)
  • National Institutes of Health (US)
  • P. J. Goldschmidt-Clermont, Division of Cardiology, Department of Medicine, and Department of Cell Biology and Anatomy, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
ORCID
Venue
Science
Publisher
American Association for the Advancement of Science (AAAS)
Published
1997-03-14
Volume
275
Issue
5306
Pages
1649-1652
ISSN
  • 0036-8075 (ISSN-L)
  • 1095-9203
DOI
10.1126/science.275.5306.1649
OpenAlex
W2072569792
Cited by
1,588
References
1
Citations by year
2026: 7 · 2025: 17 · 2024: 21 · 2023: 13 · 2022: 42 · 2021: 45 · 2020: 42 · 2019: 41 · 2018: 38 · 2017: 53 · 2016: 45 · 2015: 44 · 2014: 60 · 2013: 44 · 2012: 49
FWCI
34.37
Type
journal article
Language
en
Open access
closed
Locations
  • Science (publishedVersion)
  • PubMed (publishedVersion)
Funders
National Heart, Lung, and Blood Institute (HL52315, P50HL052315)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
Keywords
H-Ras V12, superoxide, reactive oxygen species, Ras-induced transformation, mitogenic signaling, Rac1, flavoprotein, farnesyltransferase inhibitors, diphenyleneiodonium, N-acetylcysteine, mitogen-activated protein kinase, JNK, antioxidants, cell cycle progression, NIH3T3 cells
MeSH terms
Acetylcysteine, Animals, Antioxidants, Cell Cycle, Cell Line, Transformed, Cell Transformation, Neoplastic, DNA, Electron Spin Resonance Spectroscopy, Oxidation-Reduction, Genes, ras, Superoxides, Transfection, Signal Transduction, Proto-Oncogene Proteins p21(ras), 3T3 Cells, Reactive Oxygen Species, Calcium-Calmodulin-Dependent Protein Kinases, GTP-Binding Proteins, rac GTP-Binding Proteins, Mitogen-Activated Protein Kinases, JNK Mitogen-Activated Protein Kinases, Mice

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