Comparative alterations in p53 expression and apoptosis in the irradiated rat small and large intestine

Abstract

Summary 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 criteria, and p53 expression determined by immunohistochemistry or whole-tissue Northern analysis. In the small intestine, peak levels of apoptosis appeared earlier (4 h) than in the large intestine (6 h). p53 mRNA transcript levels in small and large intestine were not significantly altered from control levels at any time after treatment. However, in treated small and large intestine, cells showed increased positivity for p53 protein, increasing 10-fold over control levels 4-5 h after irradiation. A strong spatial relationship was found between high incidence apoptosis and p53 protein positivity. We compared published data of stem cell population positions for small and large intestine with our results. Target cells for apoptosis and p53 expression occurred at approximately fifth position from the crypt base of the small intestine, a zone coincident with stem cell population. Target cell position for apoptosis and p53 expression in the large intestine was again at fifth or 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 that p53 protein is closely associated both temporally and spatially with the induction of apoptosis, and support the work of others in suggesting that p53 expression is modulated post-transcriptionally. Furthermore, our results support a hypothesis that apoptotic targeting of damaged stem cell populations, early response for apoptotic removal of DNA-damaged cells and/or early repair of these damage cells are all important parameters that determine differences in levels of tumorigenesis in the small and large intestine.

Apoptosis after gamma irradiation. Is it an important cell death modality?

“…The induction of apoptosis after some forms of DNA damage has been described by different authors to be wild-type p53 dependent (Lowe et al 1993: Yonish-Rouach et al 1993: Clarke et al 1994: Arai et al 1996. We have previously reported a close relationship between cellular radiosensitivity and p53 functionality.…”

“…p53. is known to be essential for apoptosis after y-irradiation (Lowe et al 1993: Merrit et al 1994. Arai et al, 1996.…”

Nabag (Zizyphus spina-christi) Extract Prevents Aberrant Crypt Foci Development in Colons of Azoxymethane-Treated Rats by Abrogating Oxidative Stress and inducing Apoptosis

“…Caspase-3 is also required for some typical hallmarks of apoptosis, and is indispensable for apoptotic chromatin condensation and DNA fragmentation in all cell types examined (Arai et al, 1996;Nicholson and Thornberry, 1997). Caspase-3 activation, by cleavage, has been considered as an apoptotic index, and this is essential for the formation of apoptotic bodies and commitment to loss of cell viability.…”

“…Colon carcinogenesis is a multistep process, and several lines of evidence proposed that AOM-induced colon cancer development partly by inhibiting the tumor suppressor gene p53-mediated apoptosis and by causing aberrant cell survival, thus contributed to oncongenesis (Steller, 1995;Arai et al, 1996;Wu et al, 2004). Wild type p53 has multiple functions as a tumor suppressor, including cell cycle arrest in response to DNA damage and induction of apoptosis (Giaccia and Kastan, 1998;Hirao et al, 2000).…”

SAGE transcript profiles for p53-dependent growth regulation

“…The former comparisons have been used previously for the identi®cation of potential p53-regulated genes by di erential display (Amson et al, 1996). Regardless, it is interesting that each of the known genes showing biased expression within REF-Phe132 cells has been linked to cellular growth regulation (Ambartsumian et al, 1995;Arai et al, 1996;Chambers, 1995;Guo et al, 1995;Perillo et al, 1995;Wright et al, 1996;Oates et al, 1996). Indeed, osteopontin was shown recently to be a metastasis-related factor in mammary tumors (Oates et al, 1996).…”