Editors' ChoiceCancer

Irrelevant Apoptosis?

STKE  19 Sep 2006:
Vol. 2006, Issue 353, pp. tw318
DOI: 10.1126/stke.3532006tw318

Research from two groups suggests that the ability of p53 to stimulate apoptosis in response to DNA damage is independent of its role as a tumor suppressor. p53, which is frequently mutated in human cancers, mediates cellular responses to DNA damage and to oncogenic stress. In wild-type mice, radiation elicits DNA damage-dependent cell death, whereas strains of mice that lack functional p53 are resistant to radiation-induced cell death but rapidly develop radiation-induced lymphomas. Christophorou et al. used transgenic mice that express a 4-hydroxytamoxifen (4-OHT)-sensitive fusion protein that allows p53 to be reversibly switched between functional (in the presence of 4-OHT) and nonfunctional states [homozygous p53ERTAMknockin (p53KI/KI) mice] to investigate the relation between p53’s roles in radiation-dependent apoptosis and as a tumor suppressor. p53KI/KI mice treated with 4-OHT during the 6 days before irradiation, so that functional p53 was present during irradiation, showed widespread apoptosis of primary lymphoid organs and intestinal epithelium and sustained leukocytopenia (low white blood cell count) but no protection from lymphoma, compared with p53KI/KI mice that were not treated with 4-OHT. In contrast, p53KI/KI mice in which p53 function was restored for 6 days starting 8 days after irradiation failed to experience radiation-dependent apoptosis but were protected from radiation-induced lymphomagenesis, with tumor onset delayed about 100 days. The ability of delayed p53 restoration to suppress lymphomagenesis depended on p19ARF, which is involved in oncogenic signaling to p53, rather than in the DNA damage response.

In the second study, Efeyan et al. showed that the protective effect of an extra copy of the p53 gene against spontaneous tumors and tumors following exposure to 3-methyl cholanthrene critically depended on p19ARF. Thus, both groups conclude that oncogenic signaling to p53, rather than DNA damage-dependent apoptosis, is critical to p53’s role as a tumor suppressor. Berns discusses implications of the research with regard to controlling toxic side effects of cancer therapy.

M. A. Christophorou, I. Ringshausen, A. J. Finch, L. Brown Swigart, G. I. Evan, The pathological response to DNA damage does not contribute to p53-mediated tumour suppression. Nature 443, 214-217 (2006). [PubMed]

A. Efeyan, I. Garcia-Cao, D. Herranz, S. Velasco-Miguel, M. Serrano, Policing of oncogene activity by p53. Nature 443, 159 (2006). [PubMed]

A. Berns, Can less be more for p53? Nature 443, 153-154 (2006). [PubMed]