Genetic and biochemical characterization of multidrug resistance.
Genetic and biochemical characterization of multidrug resistance.
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DOI：
10.1016/0163-7258(85)90082-8
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发表时间：
1985
影响因子：
13.5
通讯作者：
John R. Riordan;Victor Ling
中科院分区：
文献类型：
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作者：
John R. Riordan;Victor Ling
哺乳动物细胞的质膜调节对细胞过程至关重要的多种功能。这被认为是通过不同的膜和细胞质组分的动态相互作用而实现的。细胞膜的流体镶嵌模型的基本假设就是基于这样一个概念（Singer和Nicholson，1972）。虽然在阐明膜组分的生物化学和物理性质方面取得了重大进展，但这些组分如何相互作用以影响复杂的膜功能仍然不清楚。一种方法，其中持有相当大的希望描绘这样的复杂系统是一个遗传。分离由特定遗传变化产生的膜突变体，并表征其变异表型以深入了解结构和功能关系（Baker和Ling，1978）。在过去的十年中，哺乳动物细胞遗传学取得了迅速的进展，并且已经分离出非常广泛的膜改变突变体。此外，最近在分子遗传学方面的创新，例如。在分离和操纵基因方面，提供了先进的工具，并为利用这种方法提供了无与伦比的机会。本文的观点是强调遗传方法的潜力。具体而言，我们审查了一类有趣的多药耐药突变体分离培养的哺乳动物细胞。这些是膜改变的耐药突变体，其显示出对结构和功能无关的化合物的交叉耐药性和附带敏感性的意外多效性。交叉耐药的基础似乎是由于相关药物的累积减少，而侧支敏感性的基础尚不清楚。然而，这种多效性可能反映了被认为对膜功能至关重要的多分子相互作用的一些改变。在本文中，我们描述了多药耐药突变体的性质和它们的遗传特征。这些突变体的膜功能和药物转运方面的调查的应用进行了概述。还讨论了此类多药耐药突变在肿瘤疾病中的影响。
The plasma membranes of mammalian cells modulate a multiplicity of functions vital to cellular processes. This is thought to be brought about via a dynamic interaction of diverse membrane and cytoplasmic components. The essential postulate of the fluid mosaic model of cell membranes is based on such a concept (Singer and Nicholson, 1972). Although significant progress has been made in elucidating biochemical and physical properties of membrane components, how such components interact to effect intricate membrane functions is still not understood. One approach which holds considerable promise for delineating such complex systems is a genetic one. Membrane mutants resulting from specific genetic changes are isolated and their variant phenotypes characterized to gain insights into structure and function relationships (Baker and Ling, 1978). Rapid progress has been made in the past decade in mammalian cell genetics and a very broad spectrum of membrane-altered mutants has been isolated. In addition, recent innovations in molecular genetics, for example. in isolating and manipulating genes, have provided sophisticated tools and offer an unparalleled opportunity to exploit this approach. The perspective of this paper is to emphasize the potential of the genetic approach. Specifically, we review an interesting class of multidrug resistant mutants isolated in cultured mammalian cells. These are membrane-altered drug-resistant mutants that display an unanticipated pleiotropy of cross resistance and collateral sensitivity to structurally and functionally unrelated compounds. The basis of the cross resistance appears to be due to reduced accumulation of the drugs involved, while that of the collateral sensitivity is not understood. Nevertheless, this pleiotropy presumably reflects some alteration (s) in the multimolecular interactions thought to be essential for membrane functions. In this paper, we describe properties of multidrug resistance mutants and their genetic characterizations. Applications of such mutants for investigating aspects of membrane functions and drug transport are outlined. The implications of such multidrug resistance mutations in neoplastic diseases are also discussed.