P53, MUTATION FREQUENCY AND APOPTOSIS IN THE MURINE SMALL-INTESTINE

Normal function of the p53 gene is integral to the cellular response t o genotoxic stress, One prediction arising from this is that p53 defic iency results in an increased mutation frequency, However, limited evi dence has been produced in support of this idea, In order to further i nvestigate the in vivo role of p53 in surveillance against mutation, a nd particularly to address the significance of p53-dependent apoptosis , we scored mutation frequency at the Dlb-1 locus within cells of the intestinal epithelium of animals which were wild type, heterozygous or null for p53 and heterozygous (a/b) at the Dlb-1 locus, Using this as say we have shown that loss of a p53-dependent apoptotic pathway is as sociated with the detectable acquisition of mutations, but only at hig h levels of DNA damage, These results question the significance of the immediate 'wave' of p53-dependent apoptosis seen in this tissue, part icularly as there was a delayed p53-independent apoptotic pathway, We conclude that loss of p53 function only becomes relevant to the in viv o acquisition of mutations and thus tumorigenesis in certain circumsta nces.