GAMMA-RAY-INDUCED APOPTOSIS IN TRANSGENIC MICE WITH PROLIFERATIVE ABNORMALITIES IN THEIR INTESTINAL EPITHELIUM - REENTRY OF VILLUS ENTEROCYTES INTO THE CELL-CYCLE DOES NOT AFFECT THEIR RADIORESISTANCE BUT ENHANCES THE RADIOSENSITIVITY OF THE CRYPT BY INDUCING P53

The radiosensitivity of proliferating crypt epithelial cells makes the gut a major limiting factor in the use of radiotherapy for treatment of abdominal cancers, As post-mitotic epithelial cells migrate from mo use small intestinal crypts to the base of adjacent villi, they rapidl y lose their ability to undergo apoptosis in response to ionizing irra diation (IR), To determine whether this radioresistance reflects withd rawal from the cell cycle, we used a lineage-specific promoter to dire ct expression of wild type Simian virus 40 T antigen (SV40 TAgWt) to v illus, but not crypt, enterocytes in FVB/N transgenic mice, SV40 TAgWt induced, pRB-dependent, re-entry into the cell cycle is not associate d with the acquisition of IR-stimulated apoptosis 4 h or 24 h after 6 Gy or 12 Gy of gamma-irradiation, Coexpression of SV40 TAgWt and K-ras (Val12) produces dysplasia in cycling villus enterocytes but no shift towards apoptotic responsiveness to IR, These findings suggest that th e radioresistance of villus enterocytes is not simply due to their cel l cycle arrest and may be a reflection of their microenvironment, Rema rkably, reentry of villus enterocytes to the cell cycle increases the radiosensitivity of the crypt epithelium without changing Bcl-2, Bcl-x (L), Bak, or Bar expression, This effect is only manifest after IR and , based upon results obtained with mutant SV40 TAgs, depends upon reac hing a critical level of proliferation in villus enterocytes, Like the normal crypt response to IR, the villus-derived enhancement of IR-sti mulated crypt apoptosis is associated with an induction of p53 and Raf -l, and is dependent upon p53, Unlike the normal crypt response to IR, the p53 induction involves cells distributed throughout the crypt and the apoptotic response is not confined to the lower half of the crypt , These results indicate that signals initiated by cycling enterocytes can be transmitted to the crypt epithelium to induce p53 and influenc e their IR-induced apoptosis, Understanding the underlying signaling p athways may provide clues about how to modify a normal crypt's radiose nsitivity for therapeutic benefit.