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A Two-Stage, p16 INK4A - and p53-Dependent Keratinocyte Senescence Mechanism That Limits Replicative Potential Independent of Telomere Status
Open accessAbstract
With increasing frequency during serial passage in culture, primary human keratinocytes express p16(INK4A) (p16) and undergo senescence arrest. Keratinocytes engineered to express hTERT maintain long telomeres but typically are not immortalized unless, by mutation or other heritable event, they avoid or greatly reduce p16 expression. We have confirmed that keratinocytes undergo p16-related senescence during growth in culture, whether in the fibroblast feeder cell system or in the specialized K-sfm medium formulation, and that this mechanism can act as a barrier to immortalization following hTERT expression. We have characterized the p16-related arrest mechanism more precisely by interfering specifically with several regulators of cell cycle control. Epidermal, oral mucosal, corneal limbal, and conjunctival keratinocytes were transduced to express a p16-insensitive mutant cdk4 (cdk4(R24C)), to abolish p16 control, and/or a dominant negative mutant p53 (p53DD), to abolish p53 function. Expression of either cdk4(R24C) or p53DD alone had little effect on life span, but expression of both permitted cells to divide 25 to 43 population doublings (PD) beyond their normal limit. Keratinocytes from a p16(+/-) individual transduced to express p53DD alone displayed a 31-PD life span extension associated with selective growth of variants that had lost the wild-type p16 allele. Cells in which both p53 and p16 were nonfunctional divided rapidly during their extended life span but experienced telomere erosion and ultimately ceased growth with very short telomeres. Expression of hTERT in these cells immortalized them. Keratinocytes engineered to express cdk4(R24C) and hTERT but not p53DD did not exhibit an extended life span. Rare immortal variants exhibiting p53 pathway defects arose from them, however, indicating that the p53-dependent component of keratinocyte senescence is telomere independent. Mutational loss of p16 and p53 has been found to be a frequent early event in the development of squamous cell carcinoma. Our results suggest that such mutations endow keratinocytes with extended replicative potential which may serve to increase the probability of neoplastic progression.
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“Primary human fibroblasts and epithelial cells also express increasing levels of p16 during culture (Reznikoff et al., 1996; Brenner et al., 1998; Rheinwald et al., 2002; Benanti and Galloway, 2004).”
From Senescent cells, tumor suppression, and organismal aging: good citizens, bad neighbors (2005) · cites this paper as Rheinwald et al., 2002
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Cites
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The molecular biology of head and neck cancer
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Senescent cells, tumor suppression, and organismal aging: good citizens, bad neighbors
Campisi, J. (2005) · Cell · doi:10.1016/j.cell.2005.02.003 · Cited by 2,379
Ink4a/Arf expression is a biomarker of aging
Krishnamurthy, J., Torrice, C., Ramsey, M. R., Kovalev, G. I., Al-Regaiey, K., Su, L., & Sharpless, N. E. (2004) · Journal of Clinical Investigation · doi:10.1172/jci22475 · Cited by 1,486
Self-citationReversal of human cellular senescence: roles of the p53 and p16 pathways
Beauséjour, C. M., Krtolica, A., Galimi, F., Narita, M., Lowe, S. W., Yaswen, P., & Campisi, J. (2003) · The EMBO Journal · doi:10.1093/emboj/cdg417 · Cited by 1,457
Forging a signature of in vivo senescence
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Metadata
- Authors
- Rheinwald, J. G., Hahn, W. C., Ramsey, M. R., Wu, J. Y., Guo, Z., Tsao, H., De Luca, M., Catricalà, C., & O'Toole, K. M.
- Affiliations
- Brigham and Women's Hospital (US)
- Dana-Farber Cancer Institute (US)
- Harvard University (US)
- Laboratory of Tissue Engineering, Istituto Dermatopatico dell'Immacolata
- San Gallicano Hospital
- Department of Dermatology
- Corresponding author
- Rheinwald, James G.
- Venue
- Molecular and Cellular Biology
- Publisher
- Informa UK Limited
- Published
- 2002-07
- Volume
- 22
- Issue
- 14
- Pages
- 5157-5172
- ISSN
- 0270-7306 (ISSN-L)
- 1098-5549
- PMC
- PMC139780
- OpenAlex
- W2116236493
- Cited by
- 338
- References
- 79
- Citations by year
- 2026: 3 · 2025: 8 · 2024: 9 · 2023: 6 · 2022: 8 · 2021: 10 · 2020: 6 · 2019: 8 · 2018: 12 · 2017: 9 · 2016: 13 · 2015: 8 · 2014: 9 · 2013: 15 · 2012: 20
- FWCI
- 18.19
- Type
- journal article
- Language
- en
- Update notices
- correction (2002-10-01)
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Molecular and Cellular Biology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- IRIS UNIMORE (University of Modena and Reggio Emilia) (submittedVersion, cc-by)
- Funders
- National Cancer Institute (K01CA094223, CA94223)
- National Institute of Dental and Craniofacial Research (R01DE013178, P01DE012467)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › 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
- keratinocyte senescence, p16INK4a, p53, replicative senescence, hTERT, cell immortalization, CDK4, dominant-negative p53, telomere shortening, squamous cell carcinoma, cell cycle regulation, lifespan extension
- MeSH terms
- Cell Division, Cells, Cultured, Culture Media, DNA-Binding Proteins, Humans, Mutation, Proto-Oncogene Proteins, Keratinocytes, Genes, p53, Tumor Suppressor Protein p53, Telomere, Cellular Senescence, Cyclin-Dependent Kinases, Telomerase, Cyclin-Dependent Kinase Inhibitor p16, Cyclin-Dependent Kinase 4
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