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

• Published in: Oncogene Vol. 23; no. 19; pp. 3265 - 3271
• Main Authors: Komarova, Elena A, Kondratov, Roman V, Wang, Kaihua, Christov, Konstantin, Golovkina, Tatiana V, Goldblum, John R, Gudkov, Andrei V
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 22.04.2004; Nature Publishing; Nature Publishing Group
• Subjects: Animals; Apoptosis; Apoptosis - radiation effects; Benzothiazoles; Biological and medical sciences; Bone marrow; Cell Biology; Cell death; Cell growth; Cell physiology; Cell proliferation; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; Cyclin-dependent kinase inhibitor p21; Digestive System - radiation effects; Epithelium; Fundamental and applied biological sciences. Psychology; Hematopoiesis - radiation effects; Human Genetics; Internal Medicine; Ionizing radiation; Lethality; Medicine; Medicine & Public Health; Mice; Mice, Inbred C57BL; Molecular and cellular biology; Oncology; original-paper; p53 Protein; Radiation; Radiation Tolerance; Small intestine; Stem cells; Thiazoles - pharmacology; Toluene - analogs & derivatives; Toluene - pharmacology; Tumor Suppressor Protein p53 - physiology; United States > US; growth arrest; apoptosis; hematopoietic syndrome; radiation; gastro-intestinal syndrome; p53; Radiosensitivity; Rodentia; In vivo; Vertebrata; Ionizing radiation; Mammalia; TP53 Gene; Mouse; Hematopoiesis; Apoptosis; Tumor suppressor gene
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/sj.onc.1207494

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.