A mammalian lysosomal membrane protein confers multidrug resistance upon expression in Saccharomyces cerevisiae
A mammalian lysosomal membrane protein confers multidrug resistance upon expression in Saccharomyces cerevisiae
复制标题
DOI：
10.1074/jbc.274.18.12877
复制
发表时间：
1999-04-30
影响因子：
4.8
通讯作者：
Ling, V
中科院分区：
文献类型：
--
作者：
Hogue, DL;Kerby, L;Ling, V
小鼠转运蛋白（MTP）是存在于哺乳动物溶酶体和内体中的高度保守的多位膜蛋白。MTP在调节体内亚细胞分布的许多结构不同的小分子的作用已在本研究中通过其在药物敏感的酿酒酵母菌株中的表达进行了研究。令人惊讶的是，MTP在细胞内隔室的膜中的表达导致对一系列药物的细胞抗性或超敏反应，所述药物包括核苷和核碱基类似物、抗生素、蒽环类、离子载体和类固醇激素。类固醇激素的细胞内生物利用度被MTP改变，如使用酵母中的体内糖皮质激素受体驱动的报告基因测定所确定的，这表明MTP调节的药物敏感性是由于类固醇激素和其他药物的亚细胞区室化的变化而产生的。通过抑制溶酶体功能、干扰细胞内胆固醇转运或调节哺乳动物细胞的多药耐药表型的化合物，在不同程度上阻断了酵母中MTP调节的药物敏感性。这些结果表明，MTP参与了不同疏水性小分子的亚细胞区室化，并有助于哺乳动物细胞的固有药物敏感性或耐药性。
Mouse transporter protein (MTP) is a highly conserved polytopic membrane protein present in mammalian lysosomes and endosomes. The role of MTP in regulating the in vivo subcellular distribution of numerous structurally distinct small molecules has been examined in this study by its expression in a drug-sensitive strain of the yeast Saccharomyces cerevisiae. Surprisingly, the expression of MTP in membranes of an intracellular compartment resulted in a cellular resistance or hypersensitivity to a range of drugs that included nucleoside and nucleobase analogs, antibiotics, anthracyclines, ionophores, and steroid hormones. The intracellular bioavailability of steroid hormones was altered by MTP, as determined using an in vivo glucocorticoid receptor-driven reporter assay in yeast, suggesting that the MTP-regulated drug sensitivity arose due to a change in the subcellular compartmentalization of steroid hormones and other drugs. MTP-regulated drug sensitivity in yeast was blocked to varying degrees by compounds that inhibit lysosomal function, interfere with intracellular cholesterol transport, or modulate the multidrug resistance phenotype of mammalian cells. These results indicate that MTP is involved in the subcellular compartmentalization of diverse hydrophobic small molecules and contributes to the inherent drug sensitivity or resistance of the mammalian cell.