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首页> 外文期刊>Molecular and Cellular Biology >Chromosome breakage at a major fragile site associated with P-glycoprotein gene amplification in multidrug-resistant CHO cells.
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Chromosome breakage at a major fragile site associated with P-glycoprotein gene amplification in multidrug-resistant CHO cells.

机译：与多药耐药性CHO细胞中P-糖蛋白基因扩增有关的主要脆弱位点的染色体断裂。

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Recent studies of several drug-resistant Chinese hamster cell lines suggested that a breakage-fusion-bridge mechanism is frequently involved in the amplification of drug resistance genes. These observations underscore the importance of chromosome breakage in the initiation of DNA amplification in mammalian cells. However, the mechanism of this breakage is unknown. Here, we propose that the site of chromosome breakage consistent with the initial event of P-glycoprotein (P-gp) gene amplification via the breakage-fusion-bridge cycle in three independently established multidrug-resistant CHO cells was located at 1q31. This site is a major chromosome fragile site that can be induced by methotrexate and aphidicolin treatments. Pretreatments of CHO cells with methotrexate or aphidicolin enhanced the frequencies of resistance to vinca alkaloid and amplification of the P-gp gene. These observations suggest that chromosome fragile sites play a pivotal role in DNA amplification in mammalian cells. Our data are also consistent with the hypothesis that gene amplification can be initiated by stress-induced chromosome breakage that is independent of modes of action of cytotoxic agents. Drug-resistant variants may arise by their growth advantage due to overproduction of cellular target molecules via gene amplification.
机译：最近对几种耐药中国仓鼠细胞系的研究表明，断裂融合桥机制经常参与耐药基因的扩增。这些观察结果强调了在哺乳动物细胞中DNA扩增起始中染色体断裂的重要性。但是，这种破损的机理尚不清楚。在这里，我们建议在三个独立建立的多药耐药性CHO细胞中，通过断裂-融合-桥循环与P-糖蛋白（P-gp）基因扩增的初始事件一致的染色体断裂位点位于1q31。该位点是主要的染色体易碎位点，可由甲氨蝶呤和蚜虫碱处理诱导。用甲氨蝶呤或蚜虫碱预处理CHO细胞可提高对长春花生物碱的抗性频率和P-gp基因的扩增。这些观察结果表明染色体易碎位点在哺乳动物细胞的DNA扩增中起关键作用。我们的数据也与假说有关，即基因扩增可通过应激诱导的染色体断裂而启动，而染色体断裂与细胞毒性剂的作用方式无关。由于通过基因扩增产生的细胞靶分子的过量产生，它们的生长优势可能产生抗药性变体。

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