Radiosensitivity in ataxia telangiectasia fibroblasts is not associated with deregulated apoptosis.
Ataxia telangiectasia (AT) is an autosomal recessive human disorder featuring diverse clinical abnormalities including proneness to cancer and extreme sensitivity to ionizing radiation. Although cells from AT patients exhibit faulty activation of the p53 signal transduction pathway at early times after radiation exposure, it has been proposed that high levels of DNA damage persisting in AT cells may up-regulate p53 through an ATM-independent mechanism at late times after irradiation, leading to cell death by apoptosis. In this study we demonstrate that diploid skin fibroblast strains homozygous for the AT mutation fail to up-regulate p53 protein at late times (< or = 48 h) after irradiation with 60Co gamma rays. Moreover, exposure of normal and AT fibroblasts to a dose of 8 Gy does not result in a significant increase in the fraction of apoptotic cells. Since this treatment reduces the clonogenic potential of human cells by at least two orders of magnitude, we conclude that apoptosis is not the primary mechanism of cell death induced by ionizing radiation in human normal and AT fibroblast cultures. Therefore, our results are not in accordance with the current hypothesis suggesting that increased radiosensitivity of AT cells is associated with deregulated apoptosis.
Enns
L
L
Cross Cancer Institute, and Department of Oncology, University of Alberta, Edmonton, Canada.
Barley
R D
RD
Paterson
M C
MC
Mirzayans
R
R
D017209:Apoptosis / Q000502:physiology / Q000528:radiation effects*; D001260:Ataxia Telangiectasia / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D004247:DNA / Q000528:radiation effects; D004249:DNA Damage; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology* / Q000528:radiation effects*; D018922:HL-60 Cells / Q000473:pathology / Q000528:radiation effects; D006801:Humans; D011836:Radiation Tolerance; D012867:Skin / Q000166:cytology / Q000528:radiation effects; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis; D015854:Up-Regulation / Q000528:radiation effects
D016159:Tumor Suppressor Protein p53; D004247:DNA