Policing of oncogene activity by p53 (original) (raw)

Tumour biology

Nature volume 443, page 159 (2006)Cite this article

Oncogenes, rather than DNA damage, may provide the key signal to p53 to trigger tumour suppression.

Abstract

The tumour-suppressor protein p53 provides the most important genetic defence against cancer1 and is activated in response to DNA damage and to oncogenic signalling, both of which occur almost universally in malignant tumours. But the relative contribution of these two pathways in inducing p53-dependent protection against cancer is unclear. Here we show that p53-dependent protection against cancer is lost in mice that have been genetically manipulated so that their p53 is activated in response to DNA damage but not to oncogenic signalling. We conclude that oncogenic signalling is the critical event that elicits p53-dependent protection and that the DNA-damage stimulus is less important.

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Figure 1: ARF is necessary for tumour suppression by p53.

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References

  1. Harris, S. L. & Levine, A. J. Oncogene 24, 2899–2908 (2005).
    Article CAS Google Scholar
  2. Kamijo, T. et al. Cell 91, 649–659 (1997).
    Article CAS Google Scholar
  3. Garcia-Cao, I. et al. EMBO J. 21, 6225–6235 (2002).
    Article CAS Google Scholar
  4. Stott, F. J. et al. EMBO J. 17, 5001–5014 (1998).
    Article CAS Google Scholar
  5. Kamijo, T. et al. Cancer Res. 59, 2464–2469 (1999).
    CAS PubMed Google Scholar
  6. Palmero, I., Pantoja, C. & Serrano, M. Nature 395, 125–126 (1998).
    Article ADS CAS Google Scholar
  7. Zindy, F. et al. Genes Dev. 12, 2424–2433 (1998).
    Article CAS Google Scholar
  8. de Stanchina, E. et al. Genes Dev. 12, 2434–2442 (1998).
    Article CAS Google Scholar
  9. Sharpless, N. E. Mutat. Res. 576, 22–38 (2005).
    Article CAS Google Scholar
  10. Bartek, J. & Lukas, J. Cancer Cell 3, 421–429 (2003).
    Article CAS Google Scholar

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Authors and Affiliations

  1. Spanish National Cancer Centre (CNIO), Madrid, 28029, Spain
    Alejo Efeyan, Isabel Garcia-Cao, Daniel Herranz, Susana Velasco-Miguel & Manuel Serrano

Authors

  1. Alejo Efeyan
  2. Isabel Garcia-Cao
  3. Daniel Herranz
  4. Susana Velasco-Miguel
  5. Manuel Serrano

Corresponding author

Correspondence toManuel Serrano.

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The authors declare no competing financial interests.

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Efeyan, A., Garcia-Cao, I., Herranz, D. et al. Policing of oncogene activity by p53.Nature 443, 159 (2006). https://doi.org/10.1038/443159a

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Editorial Summary

The two sides of p53

The protein p53 is an important mediator of the DNA damage response and tumour suppression in vertebrates. In general, these two attributes are thought to be causally linked: p53 suppresses tumours by responding to DNA damage or genome abnormalities in tumour cells and triggering growth arrest or apoptosis. Now using a reversibly switchable endogenous p53 mouse model, Christophorou et al. show that the pathological p53-induced response to irradiation is irrelevant to p53-mediated suppression of tumours induced by that irradiation. Conversely, restoring p53 at later times avoids the pathological effects of irradiation but provides much of the tumour suppression. These data suggest that the DNA damage response and tumour suppression are unlinked activities of p53, each induced by distinct signals. A similar conclusion is drawn from a separate experiment, the absence of the tumour suppressor protein ARF was found to abolish the extra cancer-protective activity of an additional copy of p53 in mice. Again, this suggests that oncogenic signalling is critical for triggering protection by p53, whereas activation of p53 as a result of DNA damage has a lesser impact on the final development of tumours. In News and Views, Anton Berns looks at the implications of these findings for models of p53 activity.