Evans G L, Ni B, Hrycyna C A, Chen D, Ambudkar S V, Pastan I, Germann U A, Gottesman M M
Laboratory of Molecular Biology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892-4255, USA.
J Bioenerg Biomembr. 1995 Feb;27(1):43-52. doi: 10.1007/BF02110330.
Chemotherapy, though it remains one of the front-line weapons used to treat human cancer, is often ineffective due to drug resistance mechanisms manifest in tumor cells. One common pattern of drug resistance, characterized by simultaneous resistance to multiple amphipathic, but otherwise structurally dissimilar anticancer drugs, is termed multidrug resistance. Multidrug resistance in various model systems, covering the phylogenetic range from bacteria to man, can be conferred by mammalian P-glycoproteins (PGPs), often termed multidrug transporters. PGPs are 170-kD polytopic membrane proteins, predicted to consist of two homologous halves, each with six membrane spanning regions and one ATP binding site. They are members of the ATP-binding cassette (ABC) superfamily of transporters, and are known to function biochemically as energy-dependent drug efflux pumps. However, much remains to be learned about PGP structure-function relationships, membrane topology, posttranslational regulation, and bioenergetics of drug transport. Much of the recent progress in the study of the human and mouse PGPs has come from heterologous expression systems which offer the benefits of ease of genetic selection and manipulation, and/or short generation times of the organism in which PGPs are expressed, and/or high-level expression of recombinant PGP. Here we review recent studies of PGP in E. coli, baculovirus, and yeast systems and evaluate their utility for the study of PGPs, as well as other higher eukaryotic membrane proteins.
化疗虽然仍是治疗人类癌症的一线手段之一，但由于肿瘤细胞中存在耐药机制，往往效果不佳。一种常见的耐药模式，其特征是对多种两亲性但结构上不相似的抗癌药物同时耐药，被称为多药耐药。在从细菌到人类的系统发育范围内的各种模型系统中，多药耐药可由哺乳动物P-糖蛋白（PGP）引发，PGP通常被称为多药转运蛋白。PGP是170-kD的多次跨膜蛋白，预计由两个同源部分组成，每个部分有六个跨膜区域和一个ATP结合位点。它们是ATP结合盒（ABC）转运蛋白超家族的成员，已知在生化功能上作为能量依赖型药物外排泵。然而，关于PGP的结构-功能关系、膜拓扑结构、翻译后调控以及药物转运的生物能量学，仍有许多有待了解的地方。近期对人类和小鼠PGP研究的许多进展来自于异源表达系统，这些系统具有易于进行遗传选择和操作、和/或PGP所表达的生物体的代时短、和/或重组PGP的高水平表达等优点。在此，我们综述了近期在大肠杆菌、杆状病毒和酵母系统中对PGP的研究，并评估它们在PGP以及其他高等真核膜蛋白研究中的效用。
