Telomere dysfunction suppresses spontaneous tumorigenesis in vivo by initiating p53‐dependent cellular senescence
Open accessAbstract
Dysfunctional telomeres induce p53-dependent cellular senescence and apoptosis, but it is not known which function is more important for tumour suppression in vivo. We used the p53 ( R172P ) knock-in mouse, which is unable to induce apoptosis but retains intact cell-cycle arrest and cellular senescence pathways, to show that spontaneous tumorigenesis is potently repressed in Terc -/- p53 ( R172P ) mice. Tumour suppression is accompanied by global induction of p53, p21 and the senescence marker senescence-associated-beta-galactosidase. By contrast, cellular senescence was unable to suppress chemically induced skin carcinomas. These results indicate that suppression of spontaneous tumorigenesis by dysfunctional telomeres requires the activation of the p53-dependent cellular senescence pathway.
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Telomere dysfunction profoundly impairs keratinocyte transformation in the DMBA/phorbol skin model.
“demonstrating profound impairment of keratinocyte transformation in the setting of telomere dysfunction (92).”
From Telomeres and telomerase in cancer (2010) · cites this paper as [92]
In G5 TERC-/- mice, DMBA and phorbol ester treatment reduced papilloma frequency 20-fold compared with mice with intact telomere function.
“DMBA and phorbol ester treatment of G5 TERCÀ/À mice resulted in a 20-fold reduction in papilloma frequency compared with mice with intact telomere function”
From Telomeres and telomerase in cancer (2010) · cites this paper as [92]
Dysfunctional telomeres are associated with near complete suppression of tumor formation in iG1 mTerc−/− p53P/+ and iG1 mTerc−/− p53P/P mice.
“the presence of dysfunctional telomeres was associated with a near complete suppression of tumor formation in both iG1 mTerc−/− p53P/+ (0/23 mice with tumors) and iG1 mTerc−/− p53P/P mice (1/9 mice with tumors).”
From Telomere dysfunction and tumour suppression: the senescence connection (2008) · cites this paper as [58]
The iG1 mTerc−/− p53P/P mouse fails to suppress tumorigenesis in a DMBA skin carcinogenesis model.
“One surprising result is the failure of the iG1 mTerc−/− p53P/P mouse to suppress tumorigenesis in a DMBA skin carcinogenesis model58.”
From Telomere dysfunction and tumour suppression: the senescence connection (2008) · cites this paper as [58]
Cells harboring the p53 R172P mutation are incapable of activating p53-dependent apoptosis, but the p53-dependent cellular senescence pathway is intact, as induction of telomere dysfunction through TRF2-DN led to reduced proliferation and senescent cells positive for SA-β-Gal.
“Cells harboring this mutation (p53P/P) are incapable of activating p53-dependent apoptosis59, but the p53-dependent cellular senescence pathway is intact as induction of telomere dysfunction through overexpression of TRF2-DN in these cells led to dramatic reduction of cellular proliferation and the appearance of senescent cells that stain positive for SA-β-Gal58.”
From Telomere dysfunction and tumour suppression: the senescence connection (2008) · cites this paper as [58]
Dysfunctional telomere-induced senescence was accompanied by increases in senescence markers, including p53, p21, p15 and SA-β-gal activity.
“Dysfunctional telomere-induced senescence was accompanied by increases in senescence markers, including p53, p21, p15 and SA-β-gal activity”
From Telomere dysfunction and tumour suppression: the senescence connection (2008) · cites this paper as [58]
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- Authors
- Cosme‐Blanco, W., Shen, M., Lazar, A. J. F., Pathak, S., Lozano, G., Multani, A. S., & Chang, S.
- Affiliations
- The University of Texas MD Anderson Cancer Center (US)
- ORCID
- Venue
- The EMBO Reports
- Published
- 2007-03-30
- Volume
- 8
- Issue
- 5
- Pages
- 497-503
- ISSN
- 1469-221X (ISSN-L)
- 1469-3178
- PMC
- PMC1866197
- OpenAlex
- W2098951927
- Cited by
- 205
- References
- 13
- Citations by year
- 2025: 3 · 2024: 5 · 2023: 2 · 2022: 1 · 2021: 5 · 2020: 3 · 2019: 5 · 2018: 5 · 2017: 8 · 2016: 10 · 2015: 18 · 2014: 14 · 2013: 21 · 2012: 15
- FWCI
- 17.67
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- EMBO Reports (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Elsa U. Pardee Foundation
- National Cancer Institute (CA 016672, P01 CA34936-20, P01CA034936, R01CA129037, P30CA016672)
- 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
- telomere dysfunction, spontaneous tumor development, tumor suppression, p21, senescence-associated β-galactosidase, apoptosis, skin carcinogenesis, cell cycle arrest
- MeSH terms
- Animals, Embryo, Mammalian, Fibroblasts, Papilloma, Skin Neoplasms, 9,10-Dimethyl-1,2-benzanthracene, Tumor Suppressor Protein p53, Telomere, Cellular Senescence, Apoptosis, Mice
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