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首页> 外文期刊>Eukaryotic cell >Loss of Regulators of Vacuolar ATPase Function and Ceramide Synthesis Results in Multidrug Sensitivity in Schizosaccharomyces pombe
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Loss of Regulators of Vacuolar ATPase Function and Ceramide Synthesis Results in Multidrug Sensitivity in Schizosaccharomyces pombe

机译：粟酒裂殖酵母多药敏感性中空泡ATPase功能调节剂的丧失和神经酰胺合成的结果

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We undertook a screen to isolate determinants of drug resistance in fission yeast and identified two genes that, when mutated, result in sensitivity to a range of structurally unrelated compounds, some of them commonly used in the clinic. One gene, rav1, encodes the homologue of a budding yeast protein which regulates the assembly of the vacuolar ATPase. The second gene, lac1, encodes a homologue of genes that are required for ceramide synthesis. Both mutants are sensitive to the chemotherapeutic agent doxorubicin, and using the naturally fluorescent properties of this compound, we found that both rav1 and lac1 mutations result in an increased accumulation of the drug in cells. The multidrug-sensitive phenotype of rav1 mutants can be rescued by up-regulation of the lag1 gene which encodes a homologue of lac1, whereas overexpression of either lac1 or lag1 confers multidrug resistance on wild-type cells. These data suggest that changing the amount of ceramide synthase activity in cells can influence innate drug resistance. The function of Rav1 appears to be conserved, as we show that SpRav1 is part of a RAVE-like complex in fission yeast and that loss of rav1 results in defects in vacuolar (H+)-ATPase activity. Thus, we conclude that loss of normal V-ATPase function results in an increased sensitivity of Schizosaccharomyces pombe cells to drugs. The rav1 and lac1 genes are conserved in both higher eukaryotes and various pathogenic fungi. Thus, our data could provide the basis for strategies to sensitize tumor cells or drug-resistant pathogenic fungi to drugs.
机译：我们进行了筛选，以分离裂变酵母中耐药性的决定因素，并鉴定了两个基因，这些基因突变后对一系列结构无关的化合物具有敏感性，其中一些在临床上常用。 rav1 是一个基因，它编码一种发芽酵母蛋白的同源物，该蛋白调节液泡ATPase的装配。第二个基因 lac1 编码神经酰胺合成所需基因的同源物。这两个突变体均对化学治疗剂阿霉素敏感，利用该化合物的自然荧光特性，我们发现 rav1 和 lac1 突变均导致药物的积累增加在细胞中。可以通过上调编码 lac1 同源物的 lag1 基因来拯救 rav1 突变体的多药敏感表型。 lac1 或 lag1 赋予野生型细胞多药耐药性。这些数据表明，改变细胞中神经酰胺合酶活性的量可以影响先天的耐药性。 Rav1的功能似乎是保守的，因为我们证明SpRav1是裂变酵母中RAVE样复合物的一部分，而 rav1 的缺失导致液泡中的缺陷（H + ）-ATPase活性。因此，我们得出结论，正常V-ATPase功能的丧失导致裂殖酵母（Schizosaccharomyces pombe）细胞对药物的敏感性增加。 rav1 和 lac1 基因在高等真核生物和各种致病真菌中均保守。因此，我们的数据可以为使肿瘤细胞或耐药性致病真菌对药物敏感的策略提供基础。

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