Influence of Induced Reactive Oxygen Species in p53-Mediated Cell Fate Decisions
Open accessAbstract
The p53 tumor suppressor gene can induce either apoptosis or a permanent growth arrest (also termed senescence) phenotype in response to cellular stresses. We show that the increase in intracellular reactive oxygen species (ROS) associated with the magnitude of p53 protein expression correlated with the induction of either senescence or apoptosis in both normal and cancer cells. ROS inhibitors ameliorated both p53-dependent cell fates, implicating ROS accumulation as an effector in each case. The absence of Bax or PUMA strongly inhibited both p53-induced apoptosis and ROS increase, indicating an important role these p53 targets affecting mitochondrial function genes in p53-mediated ROS accumulation. Moreover, physiological p53 levels in combination with an exogenous ROS source were able to convert a p53 senescence response into apoptosis. All of these findings establish a critical role of ROS accumulation and mitochondrial function in p53-dependent cell fates and show that other ROS inducers can collaborate with p53 to influence these fate decisions. Thus, our studies imply that therapeutic agents that generate ROS are more likely to be toxic for normal cells than p53-negative tumor cells and provide a rationale for identifying therapeutic agents that do not complement p53 in ROS generation to ameliorate the cytotoxic side effects in normal cells.
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Significantly elevated p53 is directly associated with high ROS levels and the mechanism of apoptosis, whereas a mild increase in p53 expression is associated with cell senescence accompanied by a small increase in oxidative stress.
“Whereas significantly elevated p53 is directly associated with high ROS levels and the mechanism of apoptosis, a mild increase in p53 expression is associated with cell senescence accompanied by a small increase in oxidative stress (Macip et al. 2003).”
From Reactive Oxygen Species, Toxicity, Oxidative Stress, and Antioxidants: Chronic Diseases and Aging (2023) · cites this paper as Macip et al. 2003
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- Authors
- Macip, S., Igarashi, M., Berggren, P., Yu, J., Lee, S. W., & Aaronson, S. A.
- Affiliations
- Icahn School of Medicine at Mount Sinai (US)
- UPMC Hillman Cancer Center (US)
- Beth Israel Deaconess Medical Center (US)
- Corresponding author
- Aaronson, Stuart A.
- Venue
- Molecular and Cellular Biology
- Publisher
- Informa UK Limited
- Published
- 2003-12-01
- Volume
- 23
- Issue
- 23
- Pages
- 8576-8585
- ISSN
- 0270-7306 (ISSN-L)
- 1098-5549
- PMC
- PMC262651
- OpenAlex
- W2100550784
- Cited by
- 331
- References
- 59
- Citations by year
- 2026: 2 · 2025: 8 · 2024: 7 · 2023: 8 · 2022: 16 · 2021: 14 · 2020: 14 · 2019: 16 · 2018: 19 · 2017: 16 · 2016: 12 · 2015: 11 · 2014: 23 · 2013: 21 · 2012: 19
- FWCI
- 6.58
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Molecular and Cellular Biology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Leicester Research Archive (University of Leicester) (submittedVersion)
- Funders
- Johns Hopkins University (HCT116)
- Cancerfonden
- National Institutes of Health (5r01ca082211-04, CA80058)
- National Cancer Institute (R01CA078356, CA 80058, CA82211, CA85214, R01CA085214, P01CA080058, CA78356)
- Topics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Keywords
- p53, reactive oxygen species, cellular senescence, apoptosis, cell fate determination, Bax, PUMA, mitochondrial function, cancer therapy toxicity
- MeSH terms
- Base Sequence, Cell Line, DNA, Humans, Male, Mitochondria, Phenotype, Prostatic Neoplasms, Proto-Oncogene Proteins, Genes, p53, Tumor Suppressor Protein p53, Cellular Senescence, Apoptosis, Reactive Oxygen Species, Oxidative Stress, Proto-Oncogene Proteins c-bcl-2, Cell Line, Tumor, Apoptosis Regulatory Proteins, bcl-2-Associated X Protein
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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