Accumulation of class I mutant p53 and apoptosis induced by carboplatin in a human glioma cell line.
Following DNA damage, wild-type p53 increases and mediates the multiple cellular responses for the repair of DNA damage or apoptosis. Inactivation of p53 by single-amino-acid substitutions contributes to the malignant phenotype and confers resistance to therapy. Among tumor-derived p53 mutants, class I mutants still retain a native-like three-dimensional structure, whereas class II mutants have unfolded DNA-binding domains. Sequencing analysis demonstrated that a human glioma cell line (U-373MG) had only a class I mutant form of p53 of His273, which targets an Arg273 that contacts DNA but retains the native structure. In this study, we investigated the metabolic alteration of the class I mutant p53 in apoptosis of U-373MG. The cell cycle progression of U-373MG cells was affected by the addition of carboplatin, while the amount of mutant p53 also increased in their nuclei. The treated cells underwent apoptosis 48h after exposure to 50 microg/ml carboplatin. Although the exact mechanism of the class I mutant p53 in the process of apoptosis has not yet been clarified, the fact that accumulation of the activated mutant p53 in the nucleus of U-373MG is concomitant with apoptosis, just as wild-type p53 does, implies that the class I mutant p53 might retain the ability to participate in apoptosis.
D034961:Antigens, Nuclear; D000970:Antineoplastic Agents / Q000627:therapeutic use; D017209:Apoptosis; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D016190:Carboplatin / Q000627:therapeutic use*; D002470:Cell Survival / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005910:Glioma / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D020287:In Situ Nick-End Labeling; D009154:Mutation; D009687:Nuclear Proteins / Q000378:metabolism; D018807:Polymorphism, Single-Stranded Conformational; D013997:Time Factors; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism