Colon cancer is about 80 times more common than small intestinal cancer in humans and this difference has never been understood although factors such as transit time of material along the gut are thought to contribute to it. A small level of spontaneous apoptosis (programmed cell death) is observed in the proliferative compartments of both tissues and can be dramatically increased after cytotoxic insult by e.g. irradiation in mice. This apoptosis results in the elimination of the small intestinal stem cell compartment but not that of the colon where damaged cells are maintained. This, in theory, could provide one explanation for the difference in cancer incidence. The genes p53 and bcl-2 are known to induce and repress apoptosis respectively in many systems. The role of p53 and bcl-2 in the control of apoptosis in the GI tract of mice was investigated by immunohistochemistiy using antibodies against the two protein products, and by quantitating spontaneous and irradiation-induced apoptosis in p53 null and in bcl-2 null mice. In the small intestinal stem cells, where Bcl-2 is largely absent, p53 protein is detected shortly after irradiation, in contrast to the colonic stem cells, where Bcl-2 expression is generally high, and they have a more muted p53 response. This Bcl-2 expression also appears to be maintained in a number of human colonic adenomas and carcinomas examiaed and has a reciprocal relationship with p53 expression. The differential expression of these genes could potentially contribute to the difference in apoptosis sensitivity of the stem cells in the two tissues. Further evidence has come from studies of apoptosis in gene knockout mice. p53 null mice lack irradiation-induced apoptosis in both the small and large intestine although spontaneous apoptosis is unaffected in both tissues, bcl-2 null mice have increased levels of both spontaneous and irradiation-induced apoptosis in the stem cell region of the large but not the small intestine. These studies provide evidence for a role of p53 and bcl-2 in the regulation of apoptosis in the GI tract and support the hypothesis that the differential expression of apoptosis in the stem cells of the gut may contribute to the difference in cancer susceptibility of the small and large intestines.