Different impact of p53 and p21 on the radiation response of mouse tissues

Mammalian tissues differ dramatically in their sensitivity to genotoxic str ess, although the mechanisms determining these differences remain largely u nknown. To analyse the role of p53 and p21 in determination of tissue speci ficity to DNA damage in vivo, we compared the effects of gamma radiation on DNA synthesis on whole-body sections of wild type, p53-deficient and p21-d eficient mice, ii dramatic reduction in C-14-thymidine incorporation after gamma irradiation was observed in the majority of rapidly proliferating tis sues of wild type and p21(-/-) but not in p53(-/-) mice, confirming the key role of p53 in determination of tissue response to genotoxic stress vivo a nd suggesting that p53-mediated inhibition of DNA synthesis does not depend on p21, Rapid radiation induced p53-dependent apoptosis was mapped to the areas of high levels of p53 mRNA in radiation sensitive tissues analysed (w hite pulp in the spleen and bases of crypts in small intestine), indicating that p53 regulation at the mRNA level is a determinant of cellular sensiti vity to genotoxic stress. High p53 mRNA expression is inherited as a recess ive trait in cell-cell hybrids suggesting the involvement of a negative con trol mechanism in the regulation of p53 gene expression.