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atm and p53 cooperate in apoptosis and suppression of tumorigenesis, but not in resistance to acute radiation toxicity

Nature Genetics volume 16, pages 397–401 (1997)Cite this article

Abstract

Mutations in atm and p53 cause the human cancer-associated diseases ataxia-telangiectasia1 and Li-Fraumeni syndrome2,3, respectively. The two genes are believed to interact in a number of pathways4–6, including regulation of DNA damage–induced cell-cycle checkpoints7, apoptosis and radiation sensitivity8, and cellular proliferation9. Atm-null mice10–12, as well as those null for p5313,14, develop mainly T-cell lymphomas, supporting the view that these genes have similar roles in thymocyte development. To study the interactions of these two genes on an organismal level, we bred mice heterozygous for null alleles of both atm and p53 to produce all genotypic combinations. Mice doubly null for atm and p53 exhibited a dramatic acceleration of tumour formation relative to singly null mice, indicating that both genes collaborate in a significant manner to prevent tumorigenesis. With respect to their roles in apoptosis, loss of atm rendered thymocytes only partly resistant to irradiation-induced apoptosis, whereas additional loss of p53 engendered complete resistance. This implies that the irradiation-induced atm and p53 apoptotic pathways are not completely congruent. Finally—and in contrast to prior predictions4,6—atm and p53 do not appear to interact in acute radiation toxicity, suggesting a separate atm effector pathway for this DNA damage response and having implications for the prognosis and treatment of human tumours.

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References

  1. Savitsky, K. et al. A single ataxia telangiectasia gene with a product similar to PI-3 kinase. Science 268, 1749–1753 (1995).

    Article  CAS  Google Scholar 

  2. Srivastava, S., Zou, Z.Q., Pirollo, K., Blattner, W. & Chang, E.H. Germ-line transmission of a mutated p53 gene in a cancer-prone family with Li-Fraumeni syndrome. Nature 348, 747–749 (1990).

    Article  CAS  Google Scholar 

  3. Malkin, D. et al. Germ line p53 mutations in a familial syndrome of breast cancer, sarcomas, and other neoplasms. Science 250, 1233–1238 (1990).

    Article  CAS  Google Scholar 

  4. Meyn, M.S. Ataxia-telangiectasia and cellular responses to DNA damage. Cancer Res. 55, 5991–6001 (1995).

    CAS  PubMed  Google Scholar 

  5. Hawley, R.S. & Friend, S.H. Strange bedfellows in even stranger places: the role of ATM in meiotic cells, lymphocytes, tumors, and its functional links to p53. Genes Dev. 10, 2383–2388 (1996).

    Article  CAS  Google Scholar 

  6. Enoch, T. & Norbury, C. Cellular responses to DNA damage: cell-cycle checkpoints, apoptosis and the roles of p53 and ATM. Trends Biochem. Sci. 20, 426–430 (1995).

    Article  CAS  Google Scholar 

  7. Kastan, M.B. et al. A mammalian cell cycle checkpoint pathway utilizing p53 and GADD45 is defective in ataxia-telangiectasia. Cell 71, 587–597 (1992).

    Article  CAS  Google Scholar 

  8. Meyn, M.S., Strasfeld, L. & Allen, C. Testing the role of p53 in the expression of genetic instability and apoptosis in ataxia-telangiectasia. Int. J. Radiat. Biol. 66, S141–S149 (1994).

    Article  CAS  Google Scholar 

  9. Westphal, C.H. et al. Genetic interactions between atm and p53 influence cellular proliferation and irradiation-induced cell cycle checkpoints. Cancer Res. 57, 1664–1667 (1997).

    CAS  PubMed  Google Scholar 

  10. Xu, Y. & Baltimore, D. Dual roles of ATM in the cellular response to radiation and in cell growth control. Genes Dev. 10, 2401–2410 (1996).

    Article  CAS  Google Scholar 

  11. Elson, A. et al. Pleiotropic defects in ataxia-telangiectasia protein-deficient mice. Proc. Natl. Acad. Sci. USA 93, 13084–13089 (1996).

    Article  CAS  Google Scholar 

  12. Barlow, C. et al. Atm-deficient mice: a paradigm of ataxia telangiectasia. Cell 86, 159–171 (1996).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  15. Clarke, A.R. et al. Thymocyte apoptosis induced by p53-dependent and independent pathways. Nature 362, 849–852 (1993).

    Article  CAS  Google Scholar 

  16. Lowe, S.W., Schmitt, E.M., Smith, S.W., Osborne, B.A. & Jacks, T. p53 is required for radiation-induced apoptosis in mouse thymocytes. Nature 362, 847–849 (1993).

    Article  CAS  Google Scholar 

  17. Lu, X. & Lane, D.P. Differential induction of transcriptionally active p53 following UV or ionizing radiation: defects in chromosome instability syndromes. Cell 75, 765–778 (1993).

    Article  CAS  Google Scholar 

  18. Canman, C.E., Wolff, A.C., Chen, C.Y., Fornace, A.J., Jr. & Kastan, M.B. The p53-dependent G1 cell cycle checkpoint pathway and ataxia- telangiectasia. Cancer Res. 54, 5054–5058 (1994).

    CAS  PubMed  Google Scholar 

  19. Lavin, M.F. & Shiloh, Y. The genetic defect in ataxia-telangiectasia. Annu. Rev. Immunol. 15, 177–202 (1996).

    Article  Google Scholar 

  20. Donehower, L.A. et al. Effects of genetic background on tumorigenesis in p53-deficient mice. Mol. Carcinog. 14, 16–22 (1995).

    Article  CAS  Google Scholar 

  21. Gotoff, S.P., Amirmokri, E. & Liebner, E.J. Ataxia telangiectasia: neoplasia, untoward response to X-irradiation, and tuberous sclerosis. Am. J. Dis. Child. 114, 617–625 (1967).

    Article  CAS  Google Scholar 

  22. Cunliffe, P.M., Mann, J.R., Cameron, A.H. & Roberts, K.D. Radiosensitivity in ataxia-telangiectasia. Br. J. Radiol. 48, 374–376 (1975).

    Article  Google Scholar 

  23. Morgan, J.L., Holcomb, T.M. & Morissey, R.W. Radiation reaction in ataxia telangiectasia. Am. J. Dis. Child. 116, 557–559 (1968).

    CAS  PubMed  Google Scholar 

  24. Morgan, S.E., Lovly, C., Pandita, T.K., Shiloh, Y. & Kastan, M.B. Fragments of atm which have dominant-negative or complementing activity. Mol. Cell. Biol. 17, 2020–2029 (1997).

    Article  CAS  Google Scholar 

  25. Fisher, D.E. Apoptosis in cancer therapy: crossing the threshold. Cell 78, 539–542 (1994).

    Article  CAS  Google Scholar 

  26. Jacks, T. & Weinberg, R.A. Cell-cycle control and its watchman. Nature 381, 643–644 (1996).

    Article  CAS  Google Scholar 

  27. Lowe, S.W., Ruley, H.E., Jacks, T. & Housman, D.E. p53-dependent apoptosis modulates the cytotoxicity of anticancer agents. Cell 74, 957–967 (1993).

    Article  CAS  Google Scholar 

  28. Lowe, S.W. et al. p53 status and the efficacy of cancer therapy in vivo. Science 266, 807–810 (1994).

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Genetics and Howard Hughes Medical Institute, Harvard Medical School, 200 Longwood Avenue, Boston, Massachusetts, 02115, USA

    Christoph H. Westphal & Philip Leder

  2. Department of Pediatric Hematology/Oncology, Dana-Farber Cancer Institute and Children's Hospital Boston,

    Sheldon Rowan, Cornelius Schmaltz & David E. Fisher

  3. Harvard Medical School, 44 Binney Street, Boston, Massachusetts, 02115, USA

    Sheldon Rowan, Cornelius Schmaltz & David E. Fisher

  4. Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, 76100, Israel

    Ari Elson

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Westphal, C., Rowan, S., Schmaltz, C. et al. atm and p53 cooperate in apoptosis and suppression of tumorigenesis, but not in resistance to acute radiation toxicity. Nat Genet 16, 397–401 (1997). https://doi.org/10.1038/ng0897-397

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