The TP53 gene — a.k.a. 'the most frequently mutated gene in human cancer' — encodes a well-studied tumour suppressor that mediates the cellular response to stress factors such as DNA damage, hypoxia or oncogene activation. Several cancer therapeutics are being developed with the goal of restoring or increasing p53 activity. But recent findings indicate that this strategy should be reconsidered, as mice with abnormally high p53 activity are not only resistant to cancer, but also age prematurely.

Although p53 induces apoptosis in response to cellular damage, it has also been associated with replicative senescence — a terminal cell-cycle arrest state reached after a finite number of cell divisions. In the 3 January issue of Nature, Tyner et al. studied the involvement of p53 in senescence and tumour suppression using a mouse engineered to have high p53 activity. Previous attempts to transgenically overexpress p53 in mice have been unsuccessful, so Tyner et al. created — albeit unintentionally — mice expressing a mutant form of Trp53 (which encodes p53 in mice) that augments wild-type p53 activity. This mutant, called the 'm'-allele, expresses a truncated RNA encoding only the C-terminal p53 fragment.

Mice carrying the m-allele ( Trp53 +/m mice) have enhanced p53 stability and transactivation activity. In response to ionizing radiation, levels of p53 protein increased in Trp53+/m fibroblasts beyond that of wild-type fibroblasts. This led to increased expression of p53 transcriptional targets, such as WAF1 (also known as p21), a cyclin-dependent kinase inhibitor. Several other laboratories have also shown that p53 C-terminal fragments or peptides can augment wild-type p53 activity.

But what are the phenotypes of Trp53+/m mice? As expected, they are resistant to cancer — of the 35 Trp53+/m mice examined, none developed life-threatening tumours, whereas over 80% of Trp53+/− mice and over 45% of Trp53+/+ mice did. The authors showed that the enhanced tumour resistance conferred by the m-allele is dependent on the presence of the wild-type Trp53 allele, because Trp53−/m mice develop tumours at a similar rate to Trp53−/− mice. Furthermore, Trp53−/m and Trp53−/− fibroblasts are equally susceptible to transformation.

Given the enhanced tumour resistance of Trp53+/m mice, it can be predicted that they would live longer than wild-type mice. Surprisingly, the median lifespan of the Trp53+/m mice was 23% shorter than that of their Trp53+/+ littermates. Up to 12 months of age, Trp53+/m mice appear morphologically identical to controls. At 18 months, however, Trp53+/m mice undergo weight loss and develop a hunchbacked spine. The mice develop osteoporosis, hair loss, organ atrophy and reduced tolerance to stress. Histopathological examination of the Trp53+/m mice failed to reveal any specific disease-associated phenotypes.

A second line of transgenic mice containing a temperature-sensitive mutant allele of p53 also exhibits early ageing phenotypes, supporting these findings. The authors claim that some of the ageing phenotypes indicate a reduction in proliferation of stem cells, which might undergo premature replicative senescence. They propose that Trp53+/m mice might eventually reach a point in which the proliferative capacity of stem cells is so reduced that sufficient numbers of mature cells cannot be provided to maintain organ mass, function and tolerance to stress. Further studies are required to investigate the possibility that ageing might be a side effect of the natural safeguards that protect us from cancer, and to determine whether p53 contributes to premature ageing syndromes in humans.