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p53 mutant mice that display early ageing-associated phenotypes

Nature volume 415, pages 45–53 (2002)Cite this article

Abstract

The p53 tumour suppressor is activated by numerous stressors to induce apoptosis, cell cycle arrest, or senescence. To study the biological effects of altered p53 function, we generated mice with a deletion mutation in the first six exons of the p53 gene that express a truncated RNA capable of encoding a carboxy-terminal p53 fragment. This mutation confers phenotypes consistent with activated p53 rather than inactivated p53. Mutant (p53+/m) mice exhibit enhanced resistance to spontaneous tumours compared with wild-type (p53+/+) littermates. As p53+/m mice age, they display an early onset of phenotypes associated with ageing. These include reduced longevity, osteoporosis, generalized organ atrophy and a diminished stress tolerance. A second line of transgenic mice containing a temperature-sensitive mutant allele of p53 also exhibits early ageing phenotypes. These data suggest that p53 has a role in regulating organismal ageing.

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Figure 1: Structure and expression of the mutant p53 m allele.
Figure 2: Longevity in p53+/+, p53+/-, p53+/m, p53-/- and p53-/m mice.
Figure 3: Transformation and p53 response phenotypes.
Figure 4: Phenotypes of aged p53+/+ and p53+/m mice.
Figure 5: Bone phenotypes in p53+/+ and p53+/m mice.
Figure 6: Skin and hair growth phenotypes in p53+/+ and p53+/m mice.
Figure 7: Stress responses in p53+/+ and p53+/m mice.
Figure 8: Ageing-related phenotypes observed in pL53 transgenic mice.

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References

  1. Levine, A. J. p53, the cellular gatekeeper for growth and division. Cell 88, 323–331 (1997).

    Article  CAS  Google Scholar 

  2. Ko, L. J. & Prives, C. p53: puzzle and paradigm. Genes Dev. 10, 1054–1072 (1996).

    Article  CAS  Google Scholar 

  3. Giaccia, A. J. & Kastan, M. B. The complexity of p53 modulation: emerging patterns from divergent signals. Genes Dev. 12, 2973–2983 (1998).

    Article  CAS  Google Scholar 

  4. Itahana, K., Dimri, G. & Campisi, J. Regulation of cellular senescence by p53. Eur. J. Biochem. 268, 2784–2791 (2001).

    Article  CAS  Google Scholar 

  5. Atadja, P., Wong, H., Garkavtsev, I., Geillette, C. & Riabowol, K. Increased activity of p53 in senescing fibroblasts. Proc. Natl Acad. Sci. USA 92, 8348–8352 (1995).

    Article  ADS  CAS  Google Scholar 

  6. Bond, J. A. et al. Evidence that transciptional activation by p53 plays a direct role in the induction of cellular senescence. Oncogene 13, 2097–2104 (1996).

    CAS  PubMed  Google Scholar 

  7. Webley, K. et al. Posttranslational modifications of p53 in replicative senescence overlapping but distinct from those induced by DNA damage. Mol. Cell. Biol. 20, 2803–2808 (2000).

    Article  CAS  Google Scholar 

  8. Shay, J. W., Pereira-Smith, O. M. & Wright, W. E. A role for both RB and p53 in the regulation of human cellular senescence. Exp. Cell Res. 196, 33–39 (1991).

    Article  CAS  Google Scholar 

  9. Bond, J. A., Wyllie, F. S. & Wynford-Thomas, D. Escape from senescence in human diploid fibroblasts induced directly by mutant p53. Oncogene 9, 1885–1889 (1994).

    CAS  PubMed  Google Scholar 

  10. Gire, V. & Wynford-Thomas, D. Reinitiation of DNA synthesis and cell division in senescent human fibroblasts by microinjection of anti-p53 antibodies. Mol. Cell. Biol. 18, 1611–1621 (1998).

    Article  CAS  Google Scholar 

  11. Serrano, M., Lin, A. W., McCurrach, M. E., Beach, D. & Lowe, S. W. Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a. Cell 88, 593–602 (1997).

    Article  CAS  Google Scholar 

  12. Sager, R. Senescence as a mode of tumor suppression. Environ. Health Perspect. 93, 59–62 (1991).

    Article  CAS  Google Scholar 

  13. Campisi, J. Aging and cancer: the double-edged sword of replicative senescence. J. Am. Geriatric Soc. 45, 482–488 (1997).

    Article  CAS  Google Scholar 

  14. Rudolph, K. L. et al. Longevity, stress response, and cancer in aging telomerase-deficient mice. Cell 96, 701–712 (1999).

    Article  CAS  Google Scholar 

  15. Chin, L. et al. p53 deficiency rescues the adverse effects of telomere loss and cooperates with telomere dysfunction to accelerate carcinogenesis. Cell 97, 527–538 (1999).

    Article  CAS  Google Scholar 

  16. Vogel, H., Lim, D. S., Karsenty, G., Finegold, M. & Hasty, P. Deletion of Ku86 causes early onset of senescence in mice. Proc. Natl Acad. Sci. USA 96, 10770–10775 (1999).

    Article  ADS  CAS  Google Scholar 

  17. Lim, D. S. et al. Analysis of ku80-mutant mice and cells with deficient levels of p53. Mol. Cell. Biol. 20, 3772–3780 (2000).

    Article  CAS  Google Scholar 

  18. Migliaccio, E. et al. The p66shc adaptor protein controls oxidative stress response and life span in mammals. Nature 402, 309–313 (1999).

    Article  ADS  CAS  Google Scholar 

  19. Donehower, L. A. et al. Mice deficient for p53 are developmentally normal but susceptible to spontaneous tumours. Nature 356, 215–221 (1992).

    Article  ADS  CAS  Google Scholar 

  20. Jacks, T. et al. Tumor spectrum analysis in p53-mutant mice. Curr. Biol. 4, 1–7 (1994).

    Article  CAS  Google Scholar 

  21. Purdie, C. A. et al. Tumour incidence, spectrum and ploidy in mice with a large deletion in the p53 gene. Oncogene 9, 603–609 (1994).

    CAS  PubMed  Google Scholar 

  22. Lavigueur, A. et al. High incidence of lung, bone, and lymphoid tumors in transgenic mice overexpressing mutant alleles of the p53 oncogene. Mol. Cell. Biol. 9, 3982–3991 (1989).

    Article  CAS  Google Scholar 

  23. Arking, R. Biology of Aging 2nd edn 153–250 (Sinauer, Sunderland, Massachusetts, 1998).

    Google Scholar 

  24. Kalu, D. N. in Handbook of Physiology, Section 11: Aging (ed. Masoro, E. J.) 395–412 (Oxford Univ. Press, New York, 1995).

    Google Scholar 

  25. Weiss, A., Arbell, I., Steinhagen Thiessen, E. & Silbermann, M. Structural changes in aging bone: osteopenia in the proximal femurs of female mice. Bone 12, 165–172 (1991).

    Article  CAS  Google Scholar 

  26. Chuttani, A. & Gilchrest, B. A. in Handbook of Physiology, Section 11: Aging (ed. Masoro, E. J.) 309–324 (Oxford Univ. Press, New York, 1995).

    Google Scholar 

  27. Harrison, D. E. & Archer, J. R. Biomarkers of aging: tissue markers. Future research needs, strategies, directions and priorities. Exp. Gerontol. 23, 309–321 (1988).

    Article  CAS  Google Scholar 

  28. Shock, N. W. Aging of physiological systems. J. Chronic Dis. 36, 137–142 (1983).

    Article  Google Scholar 

  29. Gerstein, A. D., Phillips, T. J., Rogers, G. S. & Gilchrest, B. A. Wound healing and aging. Dermatol. Clin. 11, 749–757 (1993).

    Article  CAS  Google Scholar 

  30. Muravchik, S. in Clinical Anesthesia 3rd edn (eds Barash, P. G., Cullen, B. F. & Stoelting, R. K.) 1125–1136 (Lippincott-Raven, Philadelphia, 1997).

    Google Scholar 

  31. Harvey, R. C. & Paddleford, R. R. Management of geriatric patients. A common occurrence. Vet. Clin. North Am. Small Anim. Pract. 29, 683–699 (1999).

    Article  CAS  Google Scholar 

  32. Harrison, D. E. Evaluating functional abilities of primitive hematopoietic stem cell populations. Curr. Top. Microbiol. Immunol. 177, 13–30 (1992).

    CAS  PubMed  Google Scholar 

  33. Takeda, T. et al. Pathobiology of the senescence-accelerated mouse (SAM). Exp. Gerontol. 32, 117–127 (1997).

    Article  CAS  Google Scholar 

  34. Michalovitz, D., Halevy, O. & Oren, M. Conditional inhibition of transformation and of cell proliferation by a temperature-sensitive mutant of p53. Cell 62, 671–680 (1990).

    Article  CAS  Google Scholar 

  35. Hupp, T. R., Sparks, A. & Lane, D. P. Small peptides activate the latent sequence-specific DNA binding function of p53. Cell 83, 237–245 (1995).

    Article  CAS  Google Scholar 

  36. Jayaraman, J. & Prives, C. Activation of p53 sequence-specific DNA binding by short single strands of DNA requires the p53 C-terminus. Cell 81, 1021–1029 (1995).

    Article  CAS  Google Scholar 

  37. Muller-Tiemann, B. F., Halazonetis, T. D. & Elting, J. J. Identification of an additional negative regulatory region for p53 sequence-specific DNA binding. Proc. Natl Acad. Sci. USA 95, 6079–6084 (1998).

    Article  ADS  CAS  Google Scholar 

  38. Selivanova, G. et al. Restoration of the growth suppression function of mutant p53 by a synthetic peptide derived from the p53 C-terminal domain. Nature Med. 3, 632–638 (1997).

    Article  CAS  Google Scholar 

  39. Selivanova, G., Rybachenko, L., Jannson, E., Iotsova, V. & Wiman, K. G. Reactivation of mutant through interaction of a C-terminal preptide with the core domain. Mol. Cell. Biol. 19, 3395–3402 (1999).

    Article  CAS  Google Scholar 

  40. Hasty, P., Ramirez-Solis, R., Krumlauf, R. & Bradley, A. Introduction of a subtle mutation into the Hox-2.6 locus in embryonic stem cells. Nature 350, 243–246 (1991).

    Article  ADS  CAS  Google Scholar 

  41. Hogan, B., Beddington, R., Costantini, F. & Lacy, E. Manipulating the Mouse Embryo: A Laboratory Manual 2nd edn 189–216 (Cold Spring Harbor Laboratory Press, New York, 1994).

    Google Scholar 

  42. Venkatachalam, S. et al. Retention of wild-type p53 in tumors from p53 heterozygous mice: reduction of p53 dosage can promote cancer formation. EMBO J. 17, 4657–4667 (1998).

    Article  CAS  Google Scholar 

  43. Ducy, P. et al. Increased bone formation in osteocalcin-deficient mice. Nature 382, 448–452 (1996).

    Article  ADS  CAS  Google Scholar 

  44. Wojcik, S. M., Bundman, D. S. & Roop, D. R. Delayed wound healing in keratin 6a knockout mice. Mol. Cell. Biol. 20, 5248–5255 (2000).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank X.-J. Wang, G. Van Zant, D. Roop, R. Waikel, P. Biggs, M. Patel, S. Wojcik, R. Levasseur, V. Hortenstine, R. Ford, S. Wojcik, C. Pickering, R. Geske and M. Oren for advice and technical assistance. We also thank G. Lozano for luciferase and p53 plasmids. This study was supported by the National Cancer Institute.

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Author notes

  1. Stuart D. Tyner, Sundaresan Venkatachalam and Lawrence A. Donehower: These authors contributed equally to this work

Authors and Affiliations

  1. Cell and Molecular Biology Program,

    Stuart D. Tyner

  2. Department of Molecular Virology and Microbiology,

    Sundaresan Venkatachalam, Jene Choi, Xiongbin Lu, Gabrielle Soron, Benjamin Cooper & Lawrence A. Donehower

  3. Center for Comparative Medicine,

    Cory Brayton

  4. Scott Department of Urology,

    Sang Hee Park & Timothy Thompson

  5. Department of Human and Molecular Genetics,

    Gerard Karsenty & Allan Bradley

  6. Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, 77030, Texas, USA

    Lawrence A. Donehower

  7. Department of Cell Biology, University of Massachusetts Medical Center, Worcester, 01655, Massachusetts, USA

    Stephen Jones

  8. Marshfield Medical Research Foundation, 1000 North Oak Avenue, Marshfield, 54449, Wisconsin, USA

    Nader Ghebranious

  9. Heinrich-Pette-Institut für Experimentelle Virologie und Immunologie an der Universitat Hamburg, Martinistrasse 52, Hamburg, D-20251, Germany

    Herbert Igelmann

  10. The Sanger Centre, Wellcome Trust Genome Campus, Cambridgeshire, CB10 1SA, UK

    Gerard Karsenty, Allan Bradley & Allan Bradley

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Correspondence to Lawrence A. Donehower.

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Tyner, S., Venkatachalam, S., Choi, J. et al. p53 mutant mice that display early ageing-associated phenotypes. Nature 415, 45–53 (2002). https://doi.org/10.1038/415045a

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