p53-dependent delayed effects of radiation vary according to time of irradiation of p53 + / - mice

Abstract

We previously reported that in p53 + / − mice that had been given a whole-body dose of 3 Gy at 8 weeks of age, p53-dependent delayed effects of radiation, as manifested in T-cell receptor (TCR) variant fractions (VF) instability in mouse splenocytes, were biphasic, namely, induction of TCR-VF mutation reappeared at 44 weeks. The manifestation of the delayed effects and the measures of biological markers varied according to the timing of irradiation. We also reported that the decrease in function of the p53 gene was related to the effects of a delayed mutation. In the present study, we investigated the functions and mutations of the p53 gene in old age for p53 + / − mice following irradiation at various ages. p53 + / − mice were given a whole-body dose of 3 Gy at 8, 28 or 40 weeks of age. There were significant differences for all variables tested at 8 weeks of age. This was similarly the case for mice irradiated at 28 weeks of age, in which there were also significant differences in TCR VF and the percentage of apoptosis. In mice irradiated at 40 weeks of age, there were significant differences for all considered variables except for the p53 allele. We demonstrated that the different patterns of delayed mutation of the p53 gene at 56 weeks of age depended on the age at which mice had undergone 3-Gy whole-body irradiation. Our conclusions are limited to variation in p53-dependent delayed effects according to the time of irradiation.

PPM1D is a neuroblastoma oncogene and therapeutic target in childhood neural tumors

“…These mice developed tumors of different origin including neuroblastoma after low-dose irradiation compared to wild-type control mice. The spectrum of observed tumors was highly similar to tumors observed in p53 deficient mice or p53 deficient mice receiving irradiation[37][38][39][40][82][83][84] .Interestingly, the tumors developed in our PPM1D transgenic mice are phenotypical similar to mice with Trp53 mutations compared to Trp53 knockout mice. Mice with Trp53 deletions mainly develop lymphomas and less frequently sarcomas38,40 whereas Trp53 mutant mice, in addition to lymphomas and more frequently sarcoma, also develop carcinomas39 .…”