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Cancer

Super p53

One of the most intensively studied of cellular molecules, the p53 protein is well known for its role as a tumour suppressor: it helps to protect against cancer by regulating the response of our cells to damage and stress. A common characteristic of human cancers is the mutation, and hence inactivation, of p53, which predisposes organisms to tumours. Recent evidence suggests that the opposite may also be true — having more functional p53 than normal might prevent cancer.

Writing in EMBO Journal (21, 6225–6235; 2002), Isabel García-Cao et al. provide further support for this idea. The authors have generated mice that carry an extra, fully functional copy of the p53 gene, as seen in the image here, which shows the two normal (wild-type) p53 genes plus the extra one (the transgene) as bright dots on the blue-coloured chromosomes. These 'super-p53 mice' display an enhanced response to DNA damage. Remarkably, the animals are also less susceptible to spontaneous or carcinogen-induced tumour formation than their wild-type counterparts. These results are consistent with a report earlier this year by Stuart D. Tyner et al. (Nature 415, 45–53; 2002), which described mice carrying a truncated form of p53 that appeared to increase the activity of wild-type p53. Like the super-p53 mice, these animals were substantially protected against cancer.

Unexpectedly, however, the study by Tyner et al. suggested that preventing cancer by augmenting p53 activity may come at a price: mice carrying the truncated p53 mutant succumbed to premature ageing. This hinted that the mechanism used by p53 to protect against tumours may at the same time advance the ageing process. But in an interesting twist, García-Cao et al. now report that super-p53 mice have a normal lifespan, and show no evidence of early ageing.

How can this difference be explained? One possibility is that in the mice expressing truncated p53, p53 activity is constitutively enhanced, which might accelerate ageing. In contrast, the extra copy of p53 in the super-p53 mice is subject to normal regulation, and basal levels of p53 activity are unaltered, suggesting that p53 activity is increased only when cells encounter stress.

Together, these studies offer the exciting prospect that using drugs to augment tumour-suppressor activity could help in cancer prevention. But the differences between the two results serve as a reminder: we need to learn a lot more about tumour-suppressor function and regulation to safeguard against any potentially harmful side-effects of this approach.

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Marte, B. Super p53. Nature 420, 279 (2002). https://doi.org/10.1038/420279a

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  • DOI: https://doi.org/10.1038/420279a

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