p53 Controls Radiation-Induced Gastrointestinal Syndrome in Mice Independent of Apoptosis

Abstract

Acute exposure to ionizing radiation can cause lethal damage to the gastrointestinal (GI) tract, a condition called the GI syndrome. Whether the target cells mediating the GI syndrome are derived from the epithelium or endothelium, and whether the target cells die by apoptosis or other mechanisms, are controversial issues. Studying mouse models, we found that selective deletion of the pro-apoptotic genes Bak1 and Bax from the GI epithelium or from endothelial cells did not protect mice from developing the GI syndrome after subtotal body gamma irradiation. In contrast, selective deletion of p53 from the GI epithelium, but not endothelial cells, sensitized irradiated mice to the GI syndrome. Transgenic mice overexpressing p53 in all tissues were protected from the GI syndrome after irradiation. These results suggest that the GI syndrome is caused by death of GI epithelial cells by a mechanism that is regulated by p53 but independent of apoptosis.

The p53 pathway in hematopoiesis: lessons from mouse models, implications for humans

“…Indeed, deletion of Puma or Bax rescues the lethality caused by p53 hyper-activity in sensitive mouse models. 81,102 HSCs from Puma-null mice are highly quiescent and along with the progenitor cells are also more efficient in DNA-damage repair. 100,101 This provides further evidence in support of dominant role of apoptotic genes in hematopoietic degeneration.…”

“…The role of p53 target proapoptotic genes Puma and Bax in modulating the function of hematopoietic stem and progenitor cells in response to high-dose irradiation is already established. [100][101][102] Mice lacking either of these genes do not exhibit radiation-induced lethality (Table 1). Indeed, deletion of Puma or Bax rescues the lethality caused by p53 hyper-activity in sensitive mouse models.…”

Atm deletion with dual recombinase technology preferentially radiosensitizes tumor endothelium

“…Although these inhibitors have been shown to radiosensitize tumor cell lines and xenografts (9), concern over radiosensitization of normal tissues may limit their clinical application. For example, we previously demonstrated that cell type-specific deletion of the ATM phosphorylation target p53 sensitizes mice to radiation-induced gastrointestinal injury (10) and myocardial necrosis (11). Although Atm-knockout mice have been used to study acute radiation injury, these mice are tumor prone (12,13).…”

Correction: Radiation enteropathy—pathogenesis, treatment and prevention

“…While crypt cell apoptosis has been well described and, to some extent, taken as a measure of intestinal radiation toxicity 34 , p53 deficient mice, while exhibiting greatly diminished crypt cell apoptosis, are actually sensitized to intestinal radiation injury 35 . Moreover, using conditional Bax-deficient mice on a Bak1-deficient background, Kirsch and coworkers showed that deletion of proapoptotic genes from the intestinal epithelium did not protect from the intestinal radiation syndrome 36 . It is possible that the explanation is to be found in the effect of p53/p21 on apoptotic versus non-apoptotic cell death 37 .…”