Reassessing the role of p53 in cancer and ageing from an evolutionary perspective
Abstract
The gene p53 has been fashioned as the guardian of the genome and as prototype of the tumour suppressor gene (TSG) whose function must be inactivated in order for tumours to develop. The ubiquitous expression of truncated p53 protein isoforms, results in "premature ageing" of laboratory mouse strains engineered for expressing such isoforms. These facts have been construed in the argument that p53 evolved in order to protect organisms with renewable tissues from developing cancer yet, because p53 is also an inducer of cellular senescence or apoptosis after extensive DNA damage, it becomes a limiting factor for tissue renewal by depleting tissues from stem/precursor cells thus leading to whole-organism ageing. From that point of view p53 displays antagonist pleiotropy contributing to the establishment of degenerative diseases and ageing. Therefore, tumour suppression becomes a balancing act between cancer prevention and ageing. Nevertheless, here we present current evidence showing that the aforementioned argument is rather inconsistent and unwarranted on evolutionary grounds. The evolutionary perspective indicates that p53 evolved so as to play a subtle but very important role during development while its role as a TSG is only important in animals that are protected from most sources of extrinsic mortality, thus suggesting that p53 was primarily selected for its developmental role and not as a TSG. Therefore no real antagonist pleiotropy can be attached to p53 functions and their relationship with whole-organism ageing might be a laboratory artefact.
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p53 probably did not evolve in humans specifically to act as a tumor suppressor.
“Finally, it is unlikely that p53 was selected for as a tumor suppressor in humans, as the frequency of cancer onset is low during peak reproductive years, and increases sharply in old age [105].”
From The p53 orchestra: Mdm2 and Mdmx set the tone (2010) · cites this paper as [105]
Cancer is uncommon during the years of peak reproduction and becomes much more common late in life.
“Finally, it is unlikely that p53 was selected for as a tumor suppressor in humans, as the frequency of cancer onset is low during peak reproductive years, and increases sharply in old age [105].”
From The p53 orchestra: Mdm2 and Mdmx set the tone (2010) · cites this paper as [105]
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Maya‐Mendoza, A., Hernández-Muñoz, R. E., Gariglio, P., et al. (2005) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2005.01.011 · Cited by 23 · see citing works
p53 is a rate-limiting factor in the repair of higher-order DNA structure
Aranda‐Anzaldo, A., Orozco-Velasco, F., Garcı́a-Villa, E., & Gariglio, P. (1999) · Biochimica et Biophysica Acta (BBA) - Gene Structure and Expression · doi:10.1016/s0167-4781(99)00086-x · Cited by 21 · see citing works
Self-citationLoss of dna loop supercoiling and organization in cells infected by herpes simplex virus type 1
Aranda‐Anzaldo, A., & Dent, M. A. R. (1997) · Research in Virology · doi:10.1016/s0923-2516(97)83629-1 · Cited by 20 · see citing works
Self-citationDevelopmental noise, ageing and cancer
Aranda‐Anzaldo, A., & Dent, M. A. R. (2003) · Mechanisms of Ageing and Development · doi:10.1016/s0047-6374(03)00089-7 · Cited by 18 · see citing works
Self-citationLang, S. M., Stratakis, D. F., Freudling, A., et al. (2000) · PubMed · Cited by 15 · see citing works
Whitman, M., & McKeon, F. (2003) · Cell · doi:10.1016/s0092-8674(03)00317-9 · Cited by 6 · see citing works
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The p53 orchestra: Mdm2 and Mdmx set the tone
Wade, M., Wang, Y. V., & Wahl, G. M. (2010) · Trends in Cell Biology · doi:10.1016/j.tcb.2010.01.009 · Cited by 450 · see citing works
p53 ancestry: gazing through an evolutionary lens
Lu, W.-J., Amatruda, J. F., & Abrams, J. M. (2009) · Nature reviews. Cancer · doi:10.1038/nrc2732 · Cited by 112 · see citing works
Wang, Y. V., Leblanc, M., Fox, N., Mao, J.-H., Tinkum, K. L., Krummel, K., Engle, D., Piwnica-Worms, D., Piwnica-Worms, H., Balmain, A., et al. (2011) · Genes & Development · doi:10.1101/gad.2024411 · Cited by 53 · see citing works
- Authors
- Aranda-Anzaldo, A., & Dent, M. A. R.
- Affiliations
- Universidad Autónoma del Estado de México (MX)
- ORCID
- Dent, Myrna A.R.
- Venue
- Mechanisms of Ageing and Development
- Publisher
- Elsevier BV
- Published
- 2007-04
- Volume
- 128
- Issue
- 4
- Pages
- 293-302
- ISSN
- 0047-6374 (ISSN-L)
- OpenAlex
- W1985586273
- Cited by
- 36
- References
- 112
- Citations by year
- 2026: 3 · 2023: 1 · 2022: 1 · 2021: 2 · 2018: 3 · 2017: 1 · 2016: 2 · 2014: 1 · 2013: 2 · 2012: 2
- FWCI
- 0.50
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Mechanisms of Ageing and Development (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Keywords
- p53, tumor suppressor, aging, antagonistic pleiotropy, premature aging, cellular senescence, apoptosis, DNA damage, tissue renewal, stem cells, degenerative diseases, tumor evolution, extrinsic mortality
- MeSH terms
- Aging, Animals, Humans, Neoplasms, Neoplasms, Experimental, Tumor Suppressor Protein p53, Evolution, Molecular
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