'Super p53' mice exhibit enhanced DNA damage response, are tumor resistant and age normally
Open accessAbstract
The tumor suppressor p53 is critical in preventing cancer due to its ability to trigger proliferation arrest and cell death upon the occurrence of a variety of stresses, most notably, DNA damage and oncogenic stress. Here, we report the generation and characterization of mice carrying supernumerary copies of the p53 gene in the form of large genomic transgenes. Prior to this, we demonstrate that the p53 transgenic allele (p53-tg), when present in a p53-null genetic background, behaves as a functional replica of the endogenous gene. "Super p53" mice, carrying p53-tg alleles in addition to the two endogenous alleles, exhibit an enhanced response to DNA damage. Importantly, "super p53" mice are significantly protected from cancer when compared with normal mice. Finally, in contrast to previously reported mice with constitutively active p53, "super p53" mice do not show any indication of premature aging, probably reflecting the fact that p53 is under normal regulatory control. Together, our results prove that cancer resistance can be enhanced by a simple genetic modification and in the absence of undesirable effects.
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Only nonphysiologic activation of p53 leads to progeria.
“Only nonphysiologic activation of p53 leads to progeria, as mice expressing extra copies of wild-type p53 under the control of its own promoter do not show signs of premature aging (Garcia-Cao et al., 2002”
From DNA Repair, Genome Stability, and Aging (2005) · cites this paper as Garcia-Cao et al., 2002
The accelerated ageing phenotype in mice expressing altered isoforms of p53 might be unique to expression of these altered forms of 'superactive' p53, as simple transgenic overexpression of full-length p53 using its endogenous promoter to regulate expression does not result in a change in lifespan.
“this accelerated ageing phenotype might be unique to expression of these altered forms of 'superactive' p53, as simple transgenic overexpression of full-length p53 using its endogenous promoter to regulate expression does not result in a change in lifespan 31”
From The common biology of cancer and ageing (2007) · cites this paper as [31]
Cites
Vogelstein, B., Lane, D., & Levine, A. J. (2000) · Nature · doi:10.1038/35042675 · Cited by 6,607 · see citing works
Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a
Serrano, M., Lin, A. W., McCurrach, M. E., Beach, D., & Lowe, S. W. (1997) · Cell · doi:10.1016/s0092-8674(00)81902-9 · Cited by 5,178 · see citing works
Self-citationp53 is required for radiation-induced apoptosis in mouse thymocytes
Lowe, S. W., Schmitt, E. M., Smith, S. W., Osborne, B. A., & Jacks, T. (1993) · Nature · doi:10.1038/362847a0 · Cited by 2,864 · see citing works
Mice Lacking p21CIP1/WAF1 undergo normal development, but are defective in G1 checkpoint control
Deng, C., Zhang, P., Wade Harper, J., Elledge, S. J., & Leder, P. (1995) · Cell · doi:10.1016/0092-8674(95)90039-x · Cited by 2,113 · see citing works
p53 mutant mice that display early ageing-associated phenotypes
Tyner, S. D., Venkatachalam, S., Choi, J., Jones, S., Ghebranious, N., Igelmann, H., Lu, X., Soron, G., Cooper, B., Brayton, C., et al. (2002) · Nature · doi:10.1038/415045a · Cited by 1,459 · see citing works
Radiation-induced cell cycle arrest compromised by p21 deficiency
Brugarolas, J., Chandrasekaran, C., Gordon, J. I., Beach, D., Jacks, T., & Hannon, G. J. (1995) · Nature · doi:10.1038/377552a0 · Cited by 1,242 · see citing works
Sherr, C. J., & DePinho, R. A. (2000) · Cell · doi:10.1016/s0092-8674(00)00046-5 · Cited by 745 · see citing works
The INK4A/ARF locus and its two gene products.
Sharpless, N. E., & DePinho, R. A. (1999) · Current Opinion in Genetics & Development · doi:10.1016/s0959-437x(99)80004-5 · Cited by 533 · see citing works
Pantoja, C., & Serrano, M. (1999) · Oncogene · doi:10.1038/sj.onc.1202880 · Cited by 201 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
The DNA-damage response in human biology and disease
Jackson, S. P., & Bartek, J. (2009) · Nature · doi:10.1038/nature08467 · Cited by 6,092 · see citing works
Cellular senescence: when bad things happen to good cells
Campisi, J., & d'Adda di Fagagna, F. (2007) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2233 · Cited by 4,441 · see citing works
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 2,359 · see citing works
Four faces of cellular senescence
Rodier, F., & Campisi, J. (2011) · Journal of Cell Biology · doi:10.1083/jcb.201009094 · Cited by 2,016 · see citing works
“It should be noted that another mouse model of elevated p53 activity showed unusual cancer resistance but normal longevity, with no signs of premature aging (García-Cao et al., 2002).”
Senescence in Health and Disease
He, S., & Sharpless, N. E. (2017) · Cell · doi:10.1016/j.cell.2017.05.015 · Cited by 1,766 · see citing works
Cellular senescence in cancer and aging.
Collado, M., Blasco, M. A., & Serrano, M. (2007) · Cell · doi:10.1016/j.cell.2007.07.003 · Cited by 1,708 · see citing works
Self-citationp53 Regulates Mitochondrial Respiration
Matoba, S., Kang, J.-G., Patino, W. D., Wragg, A., Boehm, M., Gavrilova, O., Hurley, P. J., Bunz, F., & Hwang, P. M. (2006) · Science · doi:10.1126/science.1126863 · Cited by 1,650 · see citing works
Programmed cell senescence during mammalian embryonic development
Muñoz-Espín, D., Cañamero, M., Maraver, A., Gómez-López, G., Contreras, J., Murillo-Cuesta, S., Rodríguez-Baeza, A., Varela-Nieto, I., Ruberte, J., Collado, M., et al. (2013) · Cell · doi:10.1016/j.cell.2013.10.019 · Cited by 1,428 · see citing works
Self-citationSenescence and aging: Causes, consequences, and therapeutic avenues
McHugh, D., & Gil, J. (2018) · Journal of Cell Biology · doi:10.1083/jcb.201708092 · Cited by 1,233 · see citing works
The common biology of cancer and ageing
Finkel, T., Serrano, M., & Blasco, M. A. (2007) · Nature · doi:10.1038/nature05985 · Cited by 988 · see citing works
Self-citationDNA Repair, Genome Stability, and Aging
Lombard, D. B., Chua, K. F., Mostoslavsky, R., Franco, S., Gostissa, M., & Alt, F. W. (2005) · Cell · doi:10.1016/j.cell.2005.01.028 · Cited by 944 · see citing works
Kregel, K. C., & Zhang, H. J. (2007) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.00327.2006 · Cited by 883 · see citing works
Stressing the role of FoxO proteins in lifespan and disease
van der Horst, A., & Burgering, B. M. T. (2007) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2190 · Cited by 759 · see citing works
Van Remmen, H., Ikeno, Y., Hamilton, M., Pahlavani, M., Wolf, N., Thorpe, S. R., Alderson, N. L., Baynes, J. W., Epstein, C. J., Huang, T.-T., et al. (2003) · Physiological Genomics · doi:10.1152/physiolgenomics.00122.2003 · Cited by 734 · see citing works
Aging and Genome Maintenance: Lessons from the Mouse?
Hasty, P., Campisi, J., Hoeijmakers, J., van Steeg, H., & Vijg, J. (2003) · Science · doi:10.1126/science.1079161 · Cited by 553 · see citing works
Vascular Cell Senescence: Contribution to Atherosclerosis
Minamino, T., & Komuro, I. (2007) · Circulation Research · doi:10.1161/01.res.0000256837.40544.4a · Cited by 542 · see citing works
Coping with stress: multiple ways to activate p53
Horn, H. F., & Vousden, K. H. (2007) · Oncogene · doi:10.1038/sj.onc.1210263 · Cited by 522 · see citing works
Cancer and ageing: rival demons?
Campisi, J. (2003) · Nature Reviews Cancer · doi:10.1038/nrc1073 · Cited by 512 · see citing works
Telomerase Reverse Transcriptase Delays Aging in Cancer-Resistant Mice
Tomás-Loba, A., Flores, I., Fernández-Marcos, P. J., Cayuela, M. L., Maraver, A., Tejera, A., Borrás, C., Matheu, A., Klatt, P., Flores, J. M., et al. (2008) · Cell · doi:10.1016/j.cell.2008.09.034 · Cited by 484 · see citing works
Self-citationDelayed ageing through damage protection by the Arf/p53 pathway
Matheu, A., Maraver, A., Klatt, P., Flores, I., Garcia-Cao, I., Borras, C., Flores, J. M., Viña, J., Blasco, M. A., & Serrano, M. (2007) · Nature · doi:10.1038/nature05949 · Cited by 466 · see citing works
Self-citationThe p53 network: cellular and systemic DNA damage responses in aging and Cancer
Reinhardt, H. C., & Schumacher, B. (2012) · Trends in Genetics · doi:10.1016/j.tig.2011.12.002 · Cited by 458 · see citing works
Cancer as a robust system: implications for anticancer therapy
Kitano, H. (2004) · Nature reviews. Cancer · doi:10.1038/nrc1300 · Cited by 456 · see citing works
DNA damage responses and p53 in the aging process
Ou, H.-L., & Schumacher, B. (2018) · Blood · doi:10.1182/blood-2017-07-746396 · Cited by 377 · see citing works
DNA damage checkpoints in stem cells, ageing and cancer
Sperka, T., Wang, J., & Rudolph, K. L. (2012) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm3420 · Cited by 393 · see citing works
Mechanisms of cellular senescence in human and mouse cells.
Itahana, K., Campisi, J., & Dimri, G. P. (2004) · Biogerontology · doi:10.1023/b:bgen.0000017682.96395.10 · Cited by 338 · see citing works
Mechanisms that Regulate Stem Cell Aging and Life Span
Signer, R. A. J., & Morrison, S. J. (2013) · Cell Stem Cell · doi:10.1016/j.stem.2013.01.001 · Cited by 320 · see citing works
DNA damage response and metabolic disease
Shimizu, I., Yoshida, Y., Suda, M., & Minamino, T. (2014) · Cell Metabolism · doi:10.1016/j.cmet.2014.10.008 · Cited by 286 · see citing works
Telomere-driven diseases and telomere-targeting therapies
Martínez, P., & Blasco, M. A. (2017) · Journal of Cell Biology · doi:10.1083/jcb.201610111 · Cited by 257 · see citing works
“Telomerase-deficient mice show a worsening of phenotypes with increasing mouse generations owing to inherited progressively shorter telomeres, with the later generations showing severe phenotypes and premature death at pre-reproductive ages (Lee et al., 1998; Herrera et al., 1999; García-Cao et al., 2002).”
BackgroundSelf-citationMice with Pulmonary Fibrosis Driven by Telomere Dysfunction
Povedano, J. M., Martinez, P., Flores, J. M., Mulero, F., & Blasco, M. A. (2015) · Cell Reports · doi:10.1016/j.celrep.2015.06.028 · Cited by 225 · see citing works
“Importantly, telomerase-deficient mice show worsening of phenotypes with increasing mouse generations owing to inherited progressively shorter telomeres, with the later generations showing severe phenotypes and premature death at pre-reproductive ages (Garcı́a-Cao et al., 2002; Herrera et al., 1999; Lee et al., 1998).”
BackgroundSelf-citationTumor suppression and normal aging in mice with constitutively high p53 activity
Mendrysa, S. M., O'Leary, K. A., McElwee, M. K., Michalowski, J., Eisenman, R. N., Powell, D. A., & Perry, M. E. (2006) · Genes & Development · doi:10.1101/gad.1378506 · Cited by 210 · see citing works
Vascular senescence in cardiovascular and metabolic diseases
Katsuumi, G., Shimizu, I., Yoshida, Y., & Minamino, T. (2018) · Frontiers in Cardiovascular Medicine · doi:10.3389/fcvm.2018.00018 · Cited by 196 · see citing works
Cancer and ageing: convergent and divergent mechanisms
Serrano, M., & Blasco, M. A. (2007) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2242 · Cited by 182 · see citing works
Self-citationLiu, L., Charville, G. W., Cheung, T. H., Yoo, B., Santos, P. J., Schroeder, M., & Rando, T. A. (2018) · Cell Stem Cell · doi:10.1016/j.stem.2018.08.019 · Cited by 156 · see citing works
Apoptosis and aging: increased resistance to apoptosis enhances the aging process
Salminen, A., Ojala, J., & Kaarniranta, K. (2011) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-010-0597-y · Cited by 158 · see citing works
Divide and conquer: nucleotide excision repair battles cancer and ageing
Mitchell, J. R., Hoeijmakers, J. H., & Niedernhofer, L. J. (2003) · Current Opinion in Cell Biology · doi:10.1016/s0955-0674(03)00018-8 · Cited by 160 · see citing works
Eischen, C. M. (2016) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a026096 · Cited by 161 · see citing works
Insulin‐like growth factor‐1 regulates the <scp>SIRT</scp> 1‐p53 pathway in cellular senescence
Tran, D., Bergholz, J., Zhang, H., He, H., Wang, Y., Zhang, Y., Li, Q., Kirkland, J. L., & Xiao, Z. (2014) · Aging Cell · doi:10.1111/acel.12219 · Cited by 161 · see citing works
Calcium signaling alterations, oxidative stress, and autophagy in aging
Ureshino, R. P., Rocha, K. K., Lopes, G. S., Bincoletto, C., & Smaili, S. S. (2014) · Antioxidants & Redox Signaling · doi:10.1089/ars.2013.5777 · Cited by 143 · see citing works
Efeyan, A., Ortega-Molina, A., Velasco-Miguel, S., Herranz, D., Vassilev, L. T., & Serrano, M. (2007) · Cancer Research · doi:10.1158/0008-5472.can-07-0200 · Cited by 140 · see citing works
Self-citationThe p53 pathway in hematopoiesis: lessons from mouse models, implications for humans
Pant, V., Quintás-Cardama, A., & Lozano, G. (2012) · Blood · doi:10.1182/blood-2012-05-356014 · Cited by 129 · see citing works
Systemic DNA damage responses in aging and diseases
Ribezzo, F., Shiloh, Y., & Schumacher, B. (2016) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2015.12.005 · Cited by 116 · see citing works
Increased p53 activity does not accelerate telomere‐driven ageing
García‐Cao, I., García‐Cao, M., Tomás‐Loba, A., Martin‐Caballero, J., Flores, J. M., Klatt, P., Blasco, M. A., & Serrano, M. (2006) · The EMBO Reports · doi:10.1038/sj.embor.7400667 · Cited by 102 · see citing works
Self-citationGannon, H. S., Donehower, L. A., Lyle, S., & Jones, S. N. (2011) · Developmental Biology · doi:10.1016/j.ydbio.2011.02.007 · Cited by 87 · see citing works
Ohtani, N., Imamura, Y., Yamakoshi, K., Hirota, F., Nakayama, R., Kubo, Y., Ishimaru, N., Takahashi, A., Hirao, A., Shimizu, T., et al. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0706949104 · Cited by 73 · see citing works
Inhibition of Wild-Type p53-Expressing AML by the Novel Small Molecule HDM2 Inhibitor CGM097
Weisberg, E., Halilovic, E., Cooke, V. G., Nonami, A., Ren, T., Sanda, T., Simkin, I., Yuan, J., Antonakos, B., Barys, L., et al. (2015) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-15-0429 · Cited by 56 · 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
p53: Pro-aging or pro-longevity?
de Keizer, P. L. J., Laberge, R.-M., & Campisi, J. (2010) · Aging · doi:10.18632/aging.100178 · Cited by 48 · see citing works
Reassessing the role of p53 in cancer and ageing from an evolutionary perspective
Aranda-Anzaldo, A., & Dent, M. A. R. (2007) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2007.01.001 · Cited by 36 · see citing works
Modelling the p53/p66Shc Aging Pathway in the Shortest Living Vertebrate Nothobranchius Furzeri
Priami, C., De Michele, G., Cotelli, F., Cellerino, A., Giorgio, M., Pelicci, P. G., & Migliaccio, E. (2015) · Aging and Disease · doi:10.14336/ad.2014.0228 · Cited by 16 · see citing works
- Authors
- García‐Cao, I., García‐Cao, M., Martín‐Caballero, J., Criado, L. M., Klatt, P., Flores, J. M., Weill, J., Blasco, M. A., & Serrano, M.
- Affiliations
- Centro Nacional de Biotecnología (ES)
- Spanish National Cancer Research Centre (ES)
- Universidad Complutense de Madrid (ES)
- Inserm (FR)
- Corresponding author
- Serrano, Manuel
- Venue
- The EMBO Journal
- Published
- 2002-11-15
- Volume
- 21
- Issue
- 22
- Pages
- 6225-6235
- ISSN
- 0261-4189 (ISSN-L)
- 1460-2075
- PMC
- PMC137187
- OpenAlex
- W1995648202
- Cited by
- 529
- References
- 9
- Citations by year
- 2026: 6 · 2025: 10 · 2024: 10 · 2023: 20 · 2022: 16 · 2021: 11 · 2020: 18 · 2019: 20 · 2018: 15 · 2017: 28 · 2016: 23 · 2015: 24 · 2014: 21 · 2013: 24 · 2012: 33
- FWCI
- 10.79
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- The EMBO Journal (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Plan for Science, Technology and Innovation
- Centro Nacional de Biotecnología
- Topics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Keywords
- p53, DNA damage response, tumor resistance, cancer prevention, premature aging, oncogenic stress, tumor suppressor
- MeSH terms
- Aging, Animals, Urinary Bladder Neoplasms, Cell Cycle, Cells, Cultured, Crosses, Genetic, DNA Damage, Female, Fertility, Fibroblasts, Fibrosarcoma, Gene Expression Regulation, Genetic Complementation Test, Immunity, Innate, Longevity, Male, Mice, Inbred CBA, Mice, Inbred C57BL, Mice, Transgenic, Genes, p53, Tumor Suppressor Protein p53, Mice, Knockout, Transgenes, Genetic Predisposition to Disease, Mice
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