Lessons from genetically engineered animal models VII. Apoptosis in intestinal epithelium: lessons from transgenic and knockout mice

Apoptosis plays an important role in homeostasis of intestinal epithelia an d is also a stress response to toxic stimuli. Transgenic and knockout mice have provided insights into the regulation of intestinal epithelial apoptos is that could not have been obtained by cell culture techniques. Two broad types of apoptosis have been characterized: spontaneous apoptosis, which oc curs continuously at low levels in the normal, unstressed intestine, and st ress-induced apoptosis, which occurs after genotoxic insult such as exposur e to gamma radiation or DNA-damaging drugs. Spontaneous apoptosis occurs at the base of the crypt at or near the position of epithelial stem cells. Kn ockout studies have shown that spontaneous apoptosis is independent of p53 and Bar in both small and large intestine, whereas Bcl2 only regulates spon taneous apoptosis in the colon. Little is known about the regulation of the specialized form of cell death at the villus tip. In contrast, knockout st udies have demonstrated that both p53 and Bcl2 are important regulators of stress-induced apoptosis but that there are significant differences between early and late time points. Bar plays only a minor role in the regulation of stress-induced apoptosis. The cumulative effect of stress-induced apopto sis on tissue architecture is not straightforward, and cell cycle arrest al so plays a critical role. Nevertheless, p53 is an important determinant of the histopathological damage induced by 5-fluorouracil in murine intestinal epithelium. These studies have important implications for the development of more effective treatment for inflammatory bowel disease and cancer.