Dual effect of p53 on radiation sensitivity in vivo: p53 promotes hematopoietic injury, but protects from gastro-intestinal syndrome in mice

Abstract

Ionizing radiation (IR) induces p53-dependent apoptosis in radiosensitive tissues, suggesting that p53 is a determinant of radiation syndromes. In fact, p53-deficient mice survive doses of IR that cause lethal hematopoietic syndrome in wild-type animals. Surprisingly, p53 deficiency results in sensitization of mice to higher doses of IR, causing lethal gastro-intestinal (GI) syndrome. While cells in the crypts of p53-wild-type epithelium undergo prolonged growth arrest after irradiation, continuous cell proliferation ongoing in p53-deficient epithelium correlates with accelerated death of damaged cells followed by rapid destruction of villi and accelerated lethality. p21-deficient mice are also characterized by increased sensitivity to GI syndrome-inducing doses of IR. We conclude that p53/p21-mediated growth arrest plays a protective role in the epithelium of small intestine after severe doses of IR. Pharmacological inhibition of p53 by a small molecule that can rescue from lethal hematopoietic syndrome has no effect on the lethality from gastro-intestinal syndrome, presumably because of a temporary and reversible nature of its action.

P53-dependent induction of serine proteases in irradiated mouse colon

“…1A). Although past observations have not detected significant visible IR-induced injury in the large intestine of mice, 25 we show p53-dependent differences after irradiation through Ki67 staining, a marker for proliferation, and caspase-3 staining, a marker for apoptosis ( Fig. 1B and C).…”

p53 promotes cellular survival in a context-dependent manner by directly inducing the expression of haeme-oxygenase-1

“…It was noted long back that low levels of p53 can protect cells from serum withdrawal-mediated death (Lassus et al, 1996). Similarly, p53 was shown to function as a survival factor in the gastrointestinal tract under conditions of severe irradiation, which was attributed to increased sensitivity of vascular endothelial cells (Komarova et al, 2004;Burdelya et al, 2006). Furthermore, other reports have identified conditions in which absence of p53 led to elevated apoptosis, but a direct causal role for p53 in providing survival signals has not been described (Lassus et al, 1996;Lackinger and Kaina, 2000;Hermisson et al, 2006;Batista et al, 2007;Roepke et al, 2007;Roos et al, 2007).…”

Genetic dissection of the role of p21Cip1/Waf1 in p53-mediated tumour suppression

“…Tumour suppression through the p53/p21 pathway A Efeyan et al (Fan et al, 1997;Bissonnette and Hunting, 1998;Komarova et al, 2004). The oncogenic stress produced by the viral oncoprotein E1a is among the most efficient and best characterized apoptotic insults for primary MEFs and it is strictly dependent on p53 (Lowe and Ruley, 1993).…”