Cycloheximide Suppresses Radiation-induced Apoptosis in MOLT-4 Cells with Arg72 Variant of p53 through Translational Inhibition of p53 Accumulation
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概要
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The human T-cell leukemia cell line MOLT-4 is highly radiosensitive, and thus it is often used as a model of p53-dependent radiation-induced apoptosis. Two branches of the p53-mediated apoptotic pathway are reported: "transcription-dependent" and "transcription-independent." However, the relative contribution of each in different types of cells is not yet clearly defined. Moreover, recent studies have shown that the codon 72 polymorphic variants of p53 show different sensitivities to apoptosis signals. The Arg72 variant has a more potent apoptosis-inducing activity in mitochondria than the Pro72 variant. Here, we initially investigated the codon 72 polymorphism of p53 in MOLT-4 cells. Analysis of the p53 exon 4 genomic DNA sequence, which includes codon 72, revealed that MOLT-4 cells are homozygous for the allele encoding Arg72. We next investigated the involvement of the transcription-independent function of p53 using an RNA synthesis inhibitor, actinomycin D (ActD), and a protein synthesis inhibitor, cycloheximide (CHX), and found that the apoptosis was suppressed by CHX but not by ActD. We also revealed that the suppressive effect of CHX on apoptosis was specifically mediated by p53, using a p53-knockdown MOLT-4 transfectant. Furthermore, the suppressive effect of CHX on apoptosis was highly correlated with the suppression of p53 protein accumulation, and less correlated with the suppression of p53 target genes expression. These results indicated that p53 transactivation is not necessary to induce apoptosis, and that p53 protein accumulation itself is both necessary and sufficient to do so.
著者
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ENOMOTO Atsushi
Laboratory of Molecular Radiology, Center for Disease Biology and Integrative Medicine, Graduate Sch
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YAMAMOTO Shinichi
Department of Obstetrics and Gynecology, Faculty of Medicine, Kagoshima University
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IKEKITA Masahiko
Department of Applied Biological Science, Faculty of Science and Technology, Tokyo University of Sci
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MORITA Akinori
Department of Radiation Oncology, Graduate School of Medicine, The University of Tokyo
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ITO Azusa
Department of Applied Biological Science, Faculty of Agriculture, Tokyo University of Agriculture an
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OHYA Soichiro
Department of Applied Biological Science, Faculty of Science and Technology, Tokyo University of Sci
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