Coupling between gamma irradiation, p53 induction and the apoptotic response depends upon cell type in vivo

Abstract

The accumulation of p53 protein following whole body irradiation of adult mice was studied using a new polyclonal antibody to mouse p53. While dramatic accumulation of the protein was apparent in splenocytes, thymocytes and osteocytes no p53 protein accumulation was detected in the hepatocytes of the irradiated mouse. Thus, the upstream initiating signals that control the induction of p53 are controlled in a tissue specific manner. While massive apoptosis accompanies p53 induction in thymocytes and splenocytes it is not seen in the osteocytes. Thus the downstream consequences of p53 induction are also tightly controlled. These results have profound significance for an understanding of the role of the p53 tumour suppression pathway in different tissues.

DNA methylation during mouse hemopoietic differentiation and radiation-induced leukemia

“…Exposure of male mice to a minimum of 2-Gy x-rays severely affects fertility [37] (unpublished results), so the in vitro [12] and in vivo data for testes, bone marrow, and spleen (Figs. 2 and 3) [7,8,10] are consistent with the proposed correlation between methylation status and relative radiosensitivity.…”

“…For the analysis of bone marrow and spleen cell death and recovery following exposure, mice were sacrificed 4 to 14 days postirradiation and tissues harvested. Spleen weight was compared to unirradiated spleen as a measure of radiation-induced spleen cell death [8]. Bone marrow cellularity was estimated using a Scharfe System Casey 1 Coulter counter, which separates cells according to size and thus allowed white bone marrow cells (O6 mM diameter) to be distinguished and independently counted from red blood cells (!5 mM diameter) in the bone marrow.…”

“…Radiation-induced apoptosis is found in hierarchical high-turnover adult tissues that are enriched for immature stem and progenitor cells such as bone marrow, spleen, thymus, and intestine, but not in low-turnover tissues such as heart, kidney, liver, skeletal muscle, and brain [7,8]. However, the dose required to kill a radiosensitive cell varies from tissue to tissue (relative radiosensitivity), and, as exemplified by radiation-induced apoptosis in the intestine, which is confined to a small subpopulation of cells in the crypt, and with the exception of cells in the spleen and bone marrow, which are all radiosensitive, the proportion of radiosensitive cells within a high-turnover tissue also varies [4,5,8].…”

“…It should also be noted that previous studies have examined the methylation status of the thymus in adult mice [10] and since the thymus begins to atrophy and is increasingly biologically inactive from early adulthood, it is not therefore a ''high-turnover'' tissue in adults in the same way as bone marrow and spleen. Although radiation-induced apoptosis is detectable in the thymus [7,8], it is unclear what proportion of thymic cells are radiosensitive and whether this changes with age. Additionally, cells from patients with immunodeficiency, centromeric region instability, and facial anomalies syndrome (ICF) are hypomethylated due to mutations in the gene encoding DNA methyltransferase 3b and are hypersensitive to radiation [12].…”

p53 Functions in Endothelial Cells to Prevent Radiation-Induced Myocardial Injury in Mice

“…Radiation induces p53 in the heart in vivo (22) and in endothelial cells from various sources in vitro (23)(24)(25). In endothelial cells, whether p53 functions as a pro-survival or pro-death factor remains controversial.…”