Influence of the TP53 codon 72 polymorphism on the cellular responses to X-irradiation in fibroblasts from nonagenarians.
In mice, genetic modification of the gene encoding p53 affects both cancer incidence and longevity. In humans, we recently found that a TP53 codon 72 Arginine (Arg) to Proline (Pro) polymorphism affected both cancer incidence and longevity as well. The TP53 codon 72 polymorphism has previously been shown to influence the apoptotic potential of human cells in response to oxidative stress. Here, we studied the influence of this polymorphism on the cellular responses to X-irradiation of fibroblasts obtained from nonagenarians. We found that the average clonogenic survival after X-irradiation was similar for the three TP53 codon 72 genotype groups. As described before, X-irradiation did not induce an appreciable degree of apoptosis in human fibroblasts. However, percentages of senescence-associated (SA)-beta-galactosidase positive cells (p < 0.001), micronucleated cells (p < 0.001) and cells displaying abnormal nuclear morphologies (p < 0.001) significantly increased with the radiation dose. Compared to Arg/Arg fibroblasts, Pro/Pro fibroblasts exhibited higher irradiation dose-dependent increases in SA-beta-galactosidase positive cells (p(interaction) = 0.018), micronucleated cells (p(interaction) = 0.005) and cells displaying abnormal nuclear morphologies (p(interaction) = 0.029) at 3 days after irradiation. Possibly, these differences in cellular responses to stress between the TP53 codon 72 genotypes contribute to the differences in cancer incidence and longevity observed earlier for these genotypes.
den Reijer
P Martijn
PM
Department of Gerontology and Geriatrics, Leiden University Medical Centre, RC Leiden, The Netherlands.
Maier
Andrea B
AB
Westendorp
Rudi G J
RG
van Heemst
Diana
D
D000369:Aged, 80 and over; D017209:Apoptosis / Q000528:radiation effects; D002467:Cell Nucleus / Q000528:radiation effects; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000528:radiation effects; D003001:Cloning, Molecular; D003062:Codon / Q000235:genetics*; D005347:Fibroblasts / Q000378:metabolism* / Q000528:radiation effects*; D005838:Genotype; D006801:Humans; D011110:Polymorphism, Genetic / Q000235:genetics* / Q000528:radiation effects*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*; D001616:beta-Galactosidase / Q000378:metabolism
D003062:Codon; D016159:Tumor Suppressor Protein p53; D001616:beta-Galactosidase