Testing the role of p53 in the expression of genetic instability and apoptosis in ataxia-telangiectasia.
We have obtained initial evidence supporting a new model for the human disease ataxia-telangiectasia (A-T), in which the A-T and p53 genes play crucial roles in a signal transduction network that activates multiple cellular functions in response to DNA damage. Three of the model's predictions were tested. (1) Disrupting cell cycle checkpoints should increase spontaneous rates in normal cells. In order to interfere with the G1/S checkpoint, we transfected a normal cell line with vectors expressing either a dominant-negative p53ala143 mutant or a human papilloma virus E6 gene. These transformants showed 10-80-fold elevations in spontaneous recombination rates when compared with their parent. (2) A-T cells should be sensitive to DNA damage-induced apoptosis. Widespread apoptosis was detectable in four A-T fibroblast lines, but not two control lines, beginning 24 h after exposure to X-rays or streptonigrin, but not UV. Streptonigrin also induced widespread apoptosis in A-T lymphoblasts but not in control lymphoblasts. (3) Disruption of p53 function in A-T cells should increase their mutagen resistance by interfering with apoptosis. Stable transfection of either the p53143ala or the HPV18 E6 construct was associated with acquisition of streptonigrin and radiation resistance, while transfection with the p53143ala construct did not affect the streptonigrin sensitivity of a control cell line.
Department of Genetics, School of Medicine, Yale University, New Haven, CT 06510.
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Strasfeld
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Allen
D017209:Apoptosis / Q000502:physiology* / Q000528:radiation effects*; D001260:Ataxia Telangiectasia / Q000235:genetics* / Q000473:pathology*; D004247:DNA / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects; D004268:DNA-Binding Proteins; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000528:radiation effects; D016158:Genes, p53 / Q000502:physiology*; D006801:Humans; D009154:Mutation; D009856:Oncogene Proteins, Viral / Q000235:genetics; D010641:Phenotype; D011995:Recombination, Genetic; D013308:Streptonigrin / Q000494:pharmacology; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
D004268:DNA-Binding Proteins; C052603:E6 protein, Human papillomavirus type 18; D009856:Oncogene Proteins, Viral; D016159:Tumor Suppressor Protein p53; D013308:Streptonigrin; D004247:DNA