McGrath J P, Varshavsky A
Department of Biology, Massachusetts Institute of Technology, Cambridge 02139.
Nature. 1989 Aug 3;340(6232):400-4. doi: 10.1038/340400a0.
Mammalian tumours displaying multidrug resistance overexpress a plasma membrane protein (P-glycoprotein), which is encoded by the MDR1 gene and apparently functions as an energy-dependent drug efflux pump. Tissue-specific expression of MDR1 and other members of the MDR gene family has been observed in normal cells, suggesting a role for P-glycoproteins in secretion. We have isolated a gene from the yeast Saccharomyces cerevisiae that encodes a protein very similar to mammalian P-glycoproteins. Deletion of this gene resulted in sterility of MATa, but not of MAT alpha cells. Subsequent analysis revealed that the yeast P-glycoprotein is the product of the STE6 gene, a locus previously shown to be required in MATa cells for production of a-factor pheromone. Our findings suggest that the STE6 protein functions to export the hydrophobic a-factor lipopeptide in a manner analogous to the efflux of hydrophobic cytotoxic drugs catalysed by the related mammalian P-glycoprotein. Thus, the evolutionarily conserved family of MDR-like genes, including the hlyB gene of Escherichia coli and the STE6 gene of S. cerevisiae, encodes components of secretory pathways distinct from the classical, signal sequence-dependent protein translocation system.
表现出多药耐药性的哺乳动物肿瘤会过度表达一种质膜蛋白（P - 糖蛋白），该蛋白由MDR1基因编码，显然起着能量依赖性药物外排泵的作用。在正常细胞中已观察到MDR1及MDR基因家族其他成员的组织特异性表达，这表明P - 糖蛋白在分泌过程中发挥作用。我们从酿酒酵母中分离出一个基因，它编码一种与哺乳动物P - 糖蛋白非常相似的蛋白质。缺失该基因会导致MATa细胞不育，但不会导致MATα细胞不育。随后的分析表明，酵母P - 糖蛋白是STE6基因的产物，STE6基因位点先前已证明在MATa细胞中是产生a - 因子信息素所必需的。我们的研究结果表明，STE6蛋白的功能是以类似于相关哺乳动物P - 糖蛋白催化的疏水性细胞毒性药物外排的方式输出疏水性a - 因子脂肽。因此，包括大肠杆菌的hlyB基因和酿酒酵母的STE6基因在内的进化上保守的MDR样基因家族，编码了与经典的、信号序列依赖性蛋白质转运系统不同的分泌途径的组成部分。
