P53 DEPENDENCE OR EARLY APOPTOTIC AND PROLIFERATIVE RESPONSES WITHIN THE MOUSE INTESTINAL EPITHELIUM FOLLOWING GAMMA-IRRADIATION

p53 is now well characterised as a tumour suppressor gene, with loss o f normal p53 function being recorded as the commonest genetic event as sociated with human malignancy. In particular, its involvement with tu morigenesis within the intestine is well established. Normal p53 funct ion has been shown to be crucial for the induction of apoptosis in tum our cell lines, murine thymocytes and murine haematopoietic cells foll owing DNA damage. To elucidate further the role of p53 in the cellular response to DNA damage we have investigated the response to gamma-irr adiation of crypt cells in vivo from the small and large intestine of mice bearing a constitutive p53 deletion. Four hours after gamma-irrad iation, a time point at which wild type crypt cells show abundant apop tosis, crypt cells from p53-deficient mice differed in that they were completely resistant to the induction of apoptosis. The p53 dose depen dence of this phenomenon was clearly shown by the intermediate level o f apoptosis observed in p53 heterozygotes. Analysis of the mitotic ind ex and the bromodeoxyuridine labelling index showed that two other res ponses of wild type crypts to gamma-irradiation, namely the G2 block a nd the reduction in bromodeoxyuridine incorporation, were both largely intact in p53 deficient animals. These observations demonstrate that p53 function is essential for a major component of the normal response to gamma-irradiation induced DNA damage in intestinal mucosal cells, and suggest that p53 deficiency permits a population of cells bearing DNA damage to escape the normal process of deletion.