P53 Mutant Mice

As discussed earlier, p53 is a potent tumor suppressor and important for the senescence and apoptotic responses to damage. It might be expected, then, that hyperactive p53 would confer superior protection from cancer. Further, since cancer is a major age-related pathology in mice, as it is in humans, hyperactive p53 might also increase longevity. Several mouse models have been developed to test these ideas, all with surprising results.

Two transgenic mouse models were made in which a truncated form of p53 was constitutively overexpressed. One model expressed an artificially truncated p53 protein

(151), whereas the other expressed a naturally occurring isoform (152). p53 forms a tetramer, and both short p53 proteins appeared to integrate into tetrameric p53 and increase its activity. Not surprisingly, both mouse models were remarkably tumor free. Surprisingly, though, both were short lived and prematurely developed aging phenotypes including gray hair, thin skin, osteoporosis, cataracts, and diabetes. Cells from these mice were also more prone to apoptosis (151) and senescence

(152). These models suggest that tumor suppression by p53, presumably acting through cellular senescence and apoptosis, can drive aging and hence is antagonistically pleiotropic.

Two additional mouse models suggest that tumor suppression by p53 might be linked to aging, albeit more subtly. One model contained an extra copy of the p53 locus (153). In contrast to models expressing short p53 isoforms, the protein encoded by the transgenic locus was not constitutively active, although it was activated normally by damage or stress. The second model expressed a hypomorphic allele of MDM2, which degrades p53 after it responds to damage or stress. Thus, in both mouse models, p53 was not constitutively active, but rather was hyperactive only after damage or stress. Not surprisingly, these mice also were remarkably tumor free. However, they did not age prematurely and had life spans comparable to control mice, suggesting that tumor suppression need not always come at the cost of aging. On the other hand, these mice were not long lived. Given that cancer is a major cause of death in mice, it is therefore also possible that noncancer pathologies were enhanced.

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