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Nature 415, 45-53 (3 January 2002) | doi:10.1038/415045a; Received 29 June 2001; Accepted 24 October 2001

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p53 mutant mice that display early ageing-associated phenotypes

Stuart D. Tyner1,2, Sundaresan Venkatachalam2,3, Jene Choi3, Stephen Jones4, Nader Ghebranious5, Herbert Igelmann6, Xiongbin Lu3, Gabrielle Soron3, Benjamin Cooper3, Cory Brayton7, Sang Hee Park8, Timothy Thompson8, Gerard Karsenty10, Allan Bradley10,11 & Lawrence A. Donehower3,12

  1. Cell and Molecular Biology Program;
  2. Department of Molecular Virology and Microbiology
  3. Center for Comparative Medicine;
  4. Scott Department of Urology;
  5. Department of Human and Molecular Genetics; and
  6. Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA
  7. Department of Cell Biology, University of Massachusetts Medical Center, Worcester, Massachusetts 01655, USA
  8. Marshfield Medical Research Foundation, 1000 North Oak Avenue, Marshfield, Wisconsin 54449, USA
  9. Heinrich-Pette-Institut für Experimentelle Virologie und Immunologie an der Universitat Hamburg, Martinistrasse 52, D-20251 Hamburg, Germany
  10. The Sanger Centre, Wellcome Trust Genome Campus, Cambridgeshire CB10 1SA, UK
  11. These authors contributed equally to this work

Correspondence to: Lawrence A. Donehower3,12 Correspondence and requests for materials should be addressed to L.A.D. (e-mail: Email: larryd@bcm.tmc.edu).

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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.

  1. Cell and Molecular Biology Program;
  2. Department of Molecular Virology and Microbiology
  3. Center for Comparative Medicine;
  4. Scott Department of Urology;
  5. Department of Human and Molecular Genetics; and
  6. Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA
  7. Department of Cell Biology, University of Massachusetts Medical Center, Worcester, Massachusetts 01655, USA
  8. Marshfield Medical Research Foundation, 1000 North Oak Avenue, Marshfield, Wisconsin 54449, USA
  9. Heinrich-Pette-Institut für Experimentelle Virologie und Immunologie an der Universitat Hamburg, Martinistrasse 52, D-20251 Hamburg, Germany
  10. The Sanger Centre, Wellcome Trust Genome Campus, Cambridgeshire CB10 1SA, UK
  11. These authors contributed equally to this work

Correspondence to: Lawrence A. Donehower3,12 Correspondence and requests for materials should be addressed to L.A.D. (e-mail: Email: larryd@bcm.tmc.edu).