Ras Proteins Induce Senescence by Altering the Intracellular Levels of Reactive Oxygen Species
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Human diploid fibroblasts eventually lose the capacity to replicate in culture and enter a viable but nonproliferative state of senescence. Recently, it has been demonstrated that retroviral-mediated gene transfer into primary fibroblasts of an activated ras gene (V12ras) rapidly accelerates development of the senescent phenotype. Using this in vitro system, we have sought to define the mediators of Ras-induced senescence. We demonstrate that expression of V12Ras results in an increase in intracellular and in particular, mitochondrial reactive oxygen species. The ability of V12Ras to induce growth arrest and senescence is shown to be partially inhibited by coexpression of an activated rac1 gene. A more dramatic rescue of V12Ras-expressing cells is demonstrated when the cells are placed in a low oxygen environment, a condition in which reactive oxygen species production is inhibited. In addition, in a 1% oxygen environment, Ras is unable to trigger an increase in the level of the cyclin-dependent kinase inhibitor p21 or to activate the senescent program. Under normoxic (20% O2) conditions, the V12Ras senescent phenotype is demonstrated to be unaffected by scavengers of superoxide but rescued by scavengers of hydrogen peroxide. These results suggest that in normal diploid cells, Ras proteins regulate oxidant production and that a rise in intracellular H2O2 represents a critical signal mediating replicative senescence.
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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 Lee et al., 1999
Ras-induced senescence can be inhibited by using antioxidants or growing cells in low-oxygen conditions.
“Ras-induced senescence can be inhibited by using antioxidants or growing cells in low-oxygen conditions (8, 25, 33, 51).”
From Mitochondrial Dysfunction Contributes to Oncogene-Induced Senescence (2009) · cites this paper as [25]
Production of reactive oxygen species underlies the premature senescence phenotype induced by oncogenes such as ras.
“the production of reactive oxygen species seems to underlie the premature senescence phenotype induced by oncogenes such as ras (15).”
From Glycolytic Enzymes Can Modulate Cellular Life Span (2005) · cites this paper as [15]
Oncogenic ras can stimulate reactive oxygen species production.
“Because oncogenic ras can also stimulate reactive oxygen species production (15), we examined the effect of oncogenic ras on reactive oxygen species production in PGM or wild-type MEFs.”
From Glycolytic Enzymes Can Modulate Cellular Life Span (2005) · cites this paper as [15]
Oxidative stress may amplify DNA damage signaling in oncogene-overexpressing cells because high ROS levels have been detected in these cells.
“Oxidative stress also may amplify DNA damage signaling in oncogene-overexpressing cells because high ROS levels have been detected in these cells [120].”
From Mechanisms and Regulation of Cellular Senescence (2021) · cites this paper as [120]
In the early stage of senescence, mitochondria display impaired oxidative phosphorylation capacity and reduced inner membrane potential, resulting in ROS overproduction.
“In the early stage of senescence, mitochondria do not function properly and display impaired oxidative phosphorylation capacity and reduced inner membrane potential, resulting in ROS overproduction [120,121,208,211].”
From Mechanisms and Regulation of Cellular Senescence (2021) · cites this paper as [120]
ROS released by activation of Ras oncogene proteins can trigger cell senescence through activation of p53.
“ROS released by the activation of Ras oncogene proteins (H-Ras, K-Ras4A, 4B, and N-Ras), regulators of signal transduction, can also trigger cell senescence through the activation of p53 (Lee et al. 1999).”
From Reactive Oxygen Species, Toxicity, Oxidative Stress, and Antioxidants: Chronic Diseases and Aging (2023) · cites this paper as Lee et al. 1999
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- Authors
- Lee, A. C., Fenster, B. E., Ito, H., Takeda, K., Bae, N. S., Hirai, T., Yu, Z.-X., Ferrans, V. J., Howard, B. H., & Finkel, T.
- Affiliations
- National Institutes of Health (US)
- National Heart, Lung, and Blood Institute (US)
- Corresponding author
- Finkel, Toren
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 1999-03
- Volume
- 274
- Issue
- 12
- Pages
- 7936-7940
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2102088119
- Cited by
- 691
- References
- 44
- Citations by year
- 2026: 5 · 2025: 12 · 2024: 11 · 2023: 21 · 2022: 23 · 2021: 30 · 2020: 23 · 2019: 24 · 2018: 19 · 2017: 28 · 2016: 40 · 2015: 34 · 2014: 42 · 2013: 26 · 2012: 44
- FWCI
- 11.14
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Keywords
- oncogenic Ras, replicative senescence, reactive oxygen species, hydrogen peroxide, mitochondrial superoxide, Rac1, growth arrest, p21, low oxygen environment, oxidative stress signaling, human diploid fibroblasts, retroviral gene transfer
- MeSH terms
- Cells, Cultured, Fibroblasts, Flow Cytometry, Humans, Oxidation-Reduction, Oxygen, Apoptosis, Reactive Oxygen Species, ras Proteins
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