Ataxia-telangiectasia mutated is not required for p53 induction and apoptosis in irradiated epithelial tissues.
The ataxia-telangiectasia mutated (Atm) protein kinase is a central regulator of the cellular response to DNA damage. Although Atm can regulate p53, it is not known if this Atm function varies between tissues. Previous studies showed that the induction of p53 and apoptosis by whole-body ionizing radiation varies greatly between tissue and tumor types, so here we asked if Atm also had a tissue-specific role in the ionizing radiation response. Irradiated Atm-null mice showed impaired p53 induction and apoptosis in thymus, spleen, and brain. In contrast, radiation-induced p53, apoptosis, phosphorylation of Chk2, and G(2)-M cell cycle arrest were slightly delayed in Atm(-/-) epithelial cells of the small intestine but reached wild-type levels by 4 h. Radiation-induced p53 and apoptosis in Atm(-/-) hair follicle epithelial cells were not impaired at any of the time points examined. Thus, Atm is essential for radiation-induced apoptosis in lymphoid tissues but is largely dispensable in epithelial cells. This indicates that marked differences in DNA damage signaling pathways exist between tissues, which could explain some of the tissue-specific phenotypes, especially tumor suppression, associated with Atm deficiency.
Gurley
Kay E
KE
Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, C1-015, Seattle, WA 90109-1024, USA.
Kemp
Christopher J
CJ
D000818:Animals; D017209:Apoptosis / Q000502:physiology* / Q000528:radiation effects; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004817:Epidermis / Q000378:metabolism / Q000473:pathology / Q000528:radiation effects; D004848:Epithelium / Q000378:metabolism* / Q000473:pathology / Q000528:radiation effects*; D005260:Female; D018859:Hair Follicle / Q000378:metabolism / Q000473:pathology / Q000528:radiation effects; D007421:Intestine, Small / Q000378:metabolism / Q000473:pathology / Q000528:radiation effects; D008221:Lymphoid Tissue / Q000378:metabolism / Q000473:pathology / Q000528:radiation effects; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D009928:Organ Specificity; D010641:Phenotype; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D014916:Whole-Body Irradiation
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D017346:Protein Serine-Threonine Kinases