p53 codon 72 alleles influence the response to anticancer drugs in cells from aged people by regulating the cell cycle inhibitor p21^WAF1

A common polymorphism at codon 72 in p53 gene leads to an arginine to proline aminoacidic substitution which affects in an age-dependent manner the susceptibility of cells to undergo apoptosis after oxidative stress. Here we report that dermal fibroblasts from Proline allele carriers (Pro⁺) display a higher expression of p21 ^WAF1 gene, in both basal conditions and after treatment with doxorubicin or camptothecin. This phenomenon is accompanied by a lower susceptibility of Pro⁺ cells to undergo apoptosis, a lower capability to over cross G₁-S transition and an increased propensity to express markers of cell senescence, with respect to fibroblasts from Arginine homozygotes (Pro^-). All these phenomena are particularly evident in cells from centenarians. We conclude that the functional difference between the two p53 codon 72 alleles exerts a broad impact on the capability of cell from aged people to respond to stressors such as cytotoxic drugs.