COMPARATIVE ALTERATIONS IN P53 EXPRESSION AND APOPTOSIS IN THE IRRADIATED RAT SMALL AND LARGE-INTESTINE

Temporal and spatial relationships between radiation-induced apoptosis and expression of p53 mRNA and protein were compared in rat small and large intestine. Apoptosis was quantified using morphological criteri a, and p53 expression determined by immunohistochemistry or whole-tiss ue Northern analysis. In the small intestine, peak levels of apoptosis appeared earlier (4 h) than in the large intestine (6 h). p53 mRNA tr anscript levels in small and large intestine were not significantly al tered from control levels at any time after treatment. However, in tre ated small and large intestine, cells showed increased positivity for p53 protein, increasing 10-fold over control levels 4-5 h after irradi ation. A strong spatial relationship was found between high incidence apoptosis and p53 protein positivity. We compared published data of st em cell population positions for small and large intestine with our re sults. Target cells for apoptosis and p53 expression occurred at appro ximately fifth position from the crypt base of the small intestine, a zone coincident with stem cell population. Target cell position for ap optosis and p53 expression in the large intestine was again at fifth o r sixth position from the base, but this zone is not the reported stem cell position (first or second position) for large intestine. Results from our model of radiation-induced intestinal apoptosis indicate tha t p53 protein is closely associated both temporally and spatially with the induction of apoptosis, and support the work of others in suggest ing that p53 expression is modulated post-transcriptionally. Furthermo re, our results support a hypothesis that apoptotic targeting of damag ed stem cell populations, early response for apoptotic removal of DNA- damaged cells and/or early repair of these damage cells are all import ant parameters that determine differences in levels of tumorigenesis i n the small and large intestine.