Inhibition of p21‐mediated ROS accumulation can rescue p21‐induced senescence

Macip, Salvador; Igarashi, Makoto; Fang, Li; Chen, Angus; Pan, Zhen‐Qiang; Lee, Sam W.; Aaronson, Stuart A.

doi:10.1093/emboj/21.9.2180

Cited by 374Telomeres, Telomerase, and SenescenceCancer-related Molecular PathwaysGenetics, Aging, and Longevity in Model Organisms

Inhibition of p21‐mediated ROS accumulation can rescue p21‐induced senescence

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Macip, Salvador, Igarashi, Makoto, Fang, Li, Chen, Angus, Pan, Zhen‐Qiang, Lee, Sam W., Aaronson, Stuart A.·2002·The EMBO Journal

DOI 10.1093/emboj/21.9.2180PMC PMC125979

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Abstract

The cyclin-dependent kinase (CDK) inhibitor p21(Waf1/Cip1/Sdi1) was identified initially as a gene induced in senescent cells and itself has been shown to cause permanent growth arrest/senescence. Reactive oxygen species (ROS), a byproduct of oxidative processes, can also induce an irreversible growth arrest similar to senescence. Here we show that p21 increased intracellular levels of ROS both in normal fibroblasts and in p53-negative cancer cells. N-acetyl-L-cysteine, an ROS inhibitor, rescued p21-induced senescence, showing that ROS elevation is necessary for induction of the permanent growth arrest phenotype. p16(Ink4a), a CDK4- and CDK6-specific inhibitor, failed to increase ROS levels, and cell cycle arrest induced by p16 was reversible following its down-regulation, demonstrating the specificity of this p21 effect. A p21 mutant that lacked the ability to bind proliferating cell nuclear antigen (PCNA) retained the ability to induce both ROS and permanent growth arrest. All of these findings establish that p21 mediates senescence by a mechanism involving ROS accumulation which does not require either its PCNA binding or the CDK inhibitory functions shared with p16.

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Authors: Macip, S., Igarashi, M., Fang, L., Chen, A., Pan, Z., Lee, S. W., & Aaronson, S. A.
Affiliations: Icahn School of Medicine at Mount Sinai (US)
Beth Israel Deaconess Medical Center (US)
Corresponding author: Aaronson, Stuart A.
ORCID: Macip, Salvador
Pan, Zhen‐Qiang
Lee, Sam W.
Aaronson, Stuart A.
Venue: The EMBO Journal
Publisher: Springer Science and Business Media LLC
Published: 2002-05-01
Volume: 21
Issue: 9
Pages: 2180-2188
ISSN: 0261-4189 (ISSN-L)
1460-2075
DOI: 10.1093/emboj/21.9.2180
PMC: PMC125979
OpenAlex: W2133468132
Cited by: 374
References: 57
Citations by year: 2026: 15 · 2025: 12 · 2024: 18 · 2023: 20 · 2022: 24 · 2021: 19 · 2020: 13 · 2019: 20 · 2018: 23 · 2017: 19 · 2016: 14 · 2015: 20 · 2014: 20 · 2013: 14 · 2012: 14
FWCI: 6.80
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: www.springer.com/tdm (tdm)
www.springer.com/tdm (vor)
Locations: The EMBO Journal (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Leicester Research Archive (University of Leicester) (submittedVersion)
Funders: National Institutes of Health (5r01ca082211-04, 1r29gm055059-01a1, CA80058)
National Cancer Institute (R01CA078356, CA 80058, CA82211, CA85214, R01CA085214, P01CA080058, CA78356)
National Institute of General Medical Sciences (GM 55059)
Topics: Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
Keywords: p21, reactive oxygen species, cellular senescence, growth arrest, cyclin-dependent kinase inhibitors, N-acetylcysteine, p16, proliferating cell nuclear antigen, fibroblasts, oxidative stress
MeSH terms: Acetylcysteine, Fibroblasts, Humans, Tumor Cells, Cultured, Free Radical Scavengers, Cyclins, Cellular Senescence, Reactive Oxygen Species, Proliferating Cell Nuclear Antigen, Cyclin-Dependent Kinase Inhibitor p16, Cyclin-Dependent Kinase Inhibitor p21

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Inhibition of p21‐mediated ROS accumulation can rescue p21‐induced senescence

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