Loss of p16Ink4a Function Rescues Cellular Senescence Induced by Telomere Dysfunction
Open accessAbstract
p16Ink4a is a tumor suppressor and a marker for cellular senescence. Previous studies have shown that p16Ink4a plays an important role in the response to DNA damage signals caused by telomere dysfunction. In this study, we crossed Wrn−/− and p16Ink4a−/− mice to knock out the p16Ink4a function in a Wrn null background. Growth curves showed that loss of p16Ink4a could rescue the growth barriers that are observed in Wrn−/− mouse embryonic fibroblasts (MEFs). By challenging the MEFs with the global genotoxin doxorubicin, we showed that loss of p16Ink4a did not dramatically affect the global DNA damage response of Wrn−/− MEFs induced by doxorubicin. However, in response to telomere dysfunction initiated by the telomere damaging protein TRF2∆B∆M, loss of p16Ink4a could partially overcome the DNA damage response by disabling p16Ink4a up-regulation and reducing the accumulation of γ-H2AX that is observed in Wrn−/− MEFs. Furthermore, in response to TRF2∆B∆M overexpression, Wrn−/− MEFs senesced within several passages. In contrast, p16Ink4a−/− and p16Ink4a−/−Wrn−/− MEFs could continuously grow and lose expression of the exogenous TRF2∆B∆M in their late passages. In summary, our data suggest that in the context of telomere dysfunction, loss of p16Ink4a function could prevent cells from senescence. These results shed light on the anti-aging strategy through regulation of p16Ink4a expression.
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Deletion of p16 in Wrn-deficient mice with dysfunctional telomeres results in increased proliferative capacity of mouse embryonic fibroblasts.
“deletion of p16 in Wrn-deficient mice, which have dysfunctional telomeres, resulted in increased proliferative capacity of mouse embryonic fibroblasts (Zhang et al., 2012).”
From Telomeres and cell senescence—size matters not (2017) · cites this paper as Zhang et al., 2012
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Senescence-Associated Exosomes and Intercellular Communication in Cancer
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- Authors
- Zhang, X., Wu, X., Tang, W., & Luo, Y.
- Affiliations
- Kunming University of Science and Technology (CN)
- Corresponding author
- Tang, Wenru
- Luo, Ying
- Venue
- International Journal of Molecular Sciences
- Publisher
- MDPI AG
- Published
- 2012-05-16
- Volume
- 13
- Issue
- 5
- Pages
- 5866-5877
- ISSN
- 1422-0067 (ISSN-L)
- PMC
- PMC3382785
- OpenAlex
- W2039765008
- Cited by
- 23
- References
- 28
- Citations by year
- 2026: 1 · 2024: 3 · 2023: 3 · 2022: 3 · 2021: 1 · 2020: 1 · 2019: 2 · 2018: 2 · 2017: 1 · 2016: 1 · 2015: 1 · 2014: 1 · 2013: 1 · 2012: 2
- FWCI
- 1.07
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- International Journal of Molecular Sciences (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- 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
- p16INK4a, cellular senescence, telomere dysfunction, WRN, DNA damage response, TRF2, doxorubicin, γH2AX, telomere damage, anti-aging, tumor suppressor, mouse embryonic fibroblasts
- MeSH terms
- Werner Syndrome Helicase, Animals, Cells, Cultured, DNA Damage, Doxorubicin, Embryo, Mammalian, Fibroblasts, Tumor Suppressor Protein p53, Telomere, Cellular Senescence, Gene Expression Regulation, Developmental, Cyclin-Dependent Kinase Inhibitor p16, Telomeric Repeat Binding Protein 2, Mice, RecQ Helicases, Gene Knock-In Techniques
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