Heavy‐ion‐induced mutations in the gpt delta transgenic mouse: Effect of p53 gene knockout

The influence of the loss of p53 gene on heavy‐ion‐induced mutations was examined by constructing a new line of transgenic mice, p53 knockout ( p53 −/− ) gpt delta. In this mouse model, deletions in lambda DNA integrated into the mouse genome are preferentially selected as Spi ‐ phages, which can then be subjected to molecular analysis. Mice were exposed to 10 Gy of whole‐body carbon‐ion irradiation. The carbon ions were accelerated to 135 MeV/u by the RIKEN Ring Cyclotron. The p53 defect markedly enhanced the Spi ‐ mutant frequency (MF) in the kidneys of mice exposed to C‐ion irradiation: the Spi ‐ MF increased 4.4‐ and 2.8‐fold over the background level after irradiation in p53 −/− and p53 +/+ mice, respectively. There was no significant difference in the background Spi ‐ MF between p53 −/− and p53 +/+ mice. Sequence analysis of the Spi ‐ mutants indicated that the enhancement of kidney Spi ‐ MF in p53 −/− mice was primarily due to an increase in complex or rearranged‐type deletions. In contrast to the kidney, the p53 defect had no effect on the Spi ‐ MF in liver: Spi ‐ MF increased 3.0‐ and 2.7‐fold after the irradiation in p53 −/− and p53 +/+ mice, respectively. Our results suggest that p53 suppresses deletion mutations induced by heavy‐ion irradiation in an organ‐specific manner. Environ. Mol. Mutagen. 40:216–225, 2002. © 2002 Wiley‐Liss, Inc.