Altered cell cycle arrest and gene amplification potential accompany loss of wild-type p53.
Gene amplification occurs at high frequency in transformed cells (10(-3)-10(-5)), but is undetectable in normal diploid fibroblasts (less than 10(-9)). This study examines whether alterations of one or both p53 alleles were sufficient to allow gene amplification to occur. Cells retaining one wild-type p53 allele mimicked the behavior of primary diploid cells: they arrested growth in the presence of drug and failed to demonstrate amplification. Cells losing the second p53 allele failed to arrest when placed in drug and displayed the ability to amplify at a high frequency. Thus, loss of wild-type p53 may lead to amplification, possibly caused by changes in cell cycle progression. Other determinants can by-pass this p53 function, however, since tumor cells with wild-type p53 have the ability to amplify genes.
Lineberger Comprehensive Cancer Center, Department of Pathology, University of North Carolina, School of Medicine, Chapel Hill 27599-7295.
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Livingstone
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White
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Sprouse
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Livanos
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D000818:Animals; D001221:Aspartate Carbamoyltransferase / Q000037:antagonists & inhibitors / Q000235:genetics; D001224:Aspartic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D001483:Base Sequence; D002223:Carbamoyl-Phosphate Synthase (Glutamine-Hydrolyzing) / Q000037:antagonists & inhibitors / Q000235:genetics; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics*; D002478:Cells, Cultured; D002872:Chromosome Deletion; D003582:Cytogenetics; D004080:Dihydroorotase / Q000037:antagonists & inhibitors / Q000235:genetics; D004622:Embryo, Mammalian; D005347:Fibroblasts; D005784:Gene Amplification / Q000235:genetics*; D016158:Genes, p53 / Q000235:genetics / Q000502:physiology*; D005854:Germ Cells; D006579:Heterozygote; D006801:Humans; D016864:Li-Fraumeni Syndrome / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors / Q000235:genetics; D009154:Mutation; D010746:Phosphonoacetic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D014407:Tumor Cells, Cultured
C033626:CAD trifunctional enzyme; D009097:Multienzyme Complexes; D001224:Aspartic Acid; C013195:sparfosic acid; D001221:Aspartate Carbamoyltransferase; D004080:Dihydroorotase; D002223:Carbamoyl-Phosphate Synthase (Glutamine-Hydrolyzing); D010746:Phosphonoacetic Acid