GENETIC ANALYSIS OF MULTIDRUG RESISTANCE GENES

多重耐药基因的遗传分析

• 批准号: 3774914
• 负责人: M DEAN
• 金额: --
• 依托单位: DIVISION OF CANCER EPIDEMIOLOGY AND GENETICS
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3774914
• 关键词: Drosophilidae; Escherichia coli; P glycoprotein; Saccharomyces cerevisiae; adenosine triphosphate; bacterial genetics; chromosomes; computer assisted sequence analysis; eukaryote; fungal genetics; gene expression; gene mutation; genetic mapping; genome; human genetic material tag; membrane transport proteins; molecular cloning; multidrug resistance; neoplasm /cancer chemotherapy; nucleic acid probes; nucleic acid sequence; pharmacogenetics

Although a large number of tumors can be successfully treated initially with chemotherapy, the development of resistance to drugs is a major limitation. Tumors that are resistant following treatment are often resistant to more than one drug. This multidrug resistance (MDR), at least in some cases, is due to the overexpression of the P- glycoprotein/MDR genes. The MDR genes function as adenosine triphosphate (ATP)-dependent pumps that can extrude a wide variety of hydrophobic compounds from the cell. Although the normal function of the MDR genes is not known, they are part of a superfamily of membrane-bound transport molecules, the ATP-binding cassette (ABC) superfamily. Using molecular cloning techniques we have characterized several MDR-related genes from simple eukaryotic species and bacteria. The complete sequence of a Drosophila melanogaster gene (Mdr50) was determined and the gene was mapped to chromosome 2, band 50. Two genes have been characterized from the yeast, Saccromyces cerevisiae. These genes have been placed onto the genetic map and genetic disruptions of the genes have been obtained. Currently we are testing a number of chemotherapy drugs to see whether increased resistance or sensitivity is controlled by these genes. A MDR- related gene from Escherichia coli has been completely sequenced. This gene, mdl, is the largest gene of this superfamily to date that has been identified in bacteria. Mutations in the gene fail to affect the viability of bacteria, and the potential role of this gene in drug resistance is being examined. If the proteins encoded by these genes can be demonstrated to transport drugs, they may provide a better understanding of the function of MDR genes and the development of MDR. Searches of the DNA sequence data bases have revealed the presence of at least 15 uncharacterized members of the ABC superfamily in the human genome. Probes from two of these genes demonstrate that they are expressed in a tissue-specific manner, and that they map to different chromosomes. Genetic characterization of these genes may reveal a number of functionally important molecules that may be involved in the transport of substances by cells.

虽然大量的肿瘤可以成功地治疗最初 在化疗中，耐药性的发展是一个主要的问题， 限制. 治疗后耐药的肿瘤通常 对不止一种药物有抗药性。 这种多药耐药（MDR），在 至少在某些情况下，是由于P- 糖蛋白/MDR基因。 MDR基因的功能是三磷酸腺苷 （ATP）依赖性泵，可以挤出各种各样的疏水性 细胞中的化合物。 虽然MDR基因的正常功能是 未知，它们是膜结合运输超家族的一部分 ATP结合盒（ABC）超家族。 使用分子 克隆技术，我们已经表征了几个MDR相关基因， 简单的真核生物和细菌。 a的完整序列 测定了黑腹果蝇（Drosophila melanogaster）基因（Mdr 50）， 定位于2号染色体50带 两个基因的特征已被确定 酿酒酵母 这些基因被植入到 获得了这些基因的遗传图谱和遗传破坏。 目前，我们正在测试一些化疗药物，看看是否 增加的抗性或敏感性由这些基因控制。 MDR- 大肠杆菌的相关基因已完全测序。 这 mdl基因是迄今为止该超家族中最大的基因， 在细菌中发现。 基因突变不能影响 细菌的生存能力，以及该基因在药物治疗中的潜在作用 正在审查阻力。 如果这些基因编码的蛋白质 被证明可以运输药物，它们可以提供更好的 了解MDR基因的功能和MDR的发生发展。 对DNA序列数据库的分析显示， 人类中至少有15个未表征的ABC超家族成员 基因组 来自其中两个基因的探针表明， 以组织特异性的方式表达，并且它们映射到不同的 染色体 这些基因的遗传特征可能揭示了一些 可能参与运输的重要分子 物质的细胞。