GENETIC ANALYSIS OF MULTIDRUG RESISTANCE GENES

多重耐药基因的遗传分析

• 批准号: 2463679
• 负责人: M DEAN
• 金额: --
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 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/2463679
• 关键词: Caenorhabditis elegans; P glycoprotein; adenosine triphosphate; cadmium; drug screening /evaluation; gene expression; genetic models; human genetic material tag; membrane transport proteins; model design /development; molecular cloning; multidrug resistance; neoplasm /cancer chemotherapy; neoplasm /cancer genetics; pharmacogenetics

Resistance of tumors to several drugs (Multidrug Resistance, MDR) is a major limitation of cancer chemotherapy. In some tumors MDR is due to the overexpression of the P-glycoprotein/(PGP)MDR gene, or the multidrug resistance-related protein (MRP). PGP and MRP are members of a family of adenosine triphosphate (ATP)-dependent transporters and have been shown to cause the efflux of a large variety of compounds from the cell. The gene family is known as the ATP-binding cassette (ABC) family, and its members transport multiple diverse compounds across the membranes of cells and tissues. Human ABC genes are involved in a number of diseases including cystic fibrosis, adrenoleuko-dystrophy, and familial persistent hyperinsulinemic hypoglycemia. To identify new genes involved in multidrug resistance we have characterized 21 new human ABC genes. The genetic location of each of these genes as well as their expression pattern has been determined. One of these genes, MRP3, is expressed predominantly in the liver. The expression of this gene in a panel of cells used for the screening of 40,000 potential chemotherapeutic families has been assessed. This data provides information on the nature of molecules transported by MRP3. We have cloned a Caenorhabditis elegans homolog of the human MRP gene mrp-1 and determined the expression of the gene in the cells of this nematode. The mrp-1 gene is expressed in several secretory cells in the animal, consistent with the gene playing a role in the removal of toxic compounds. Genetic disruption of the mrp-1 gene demonstrates that it is essential for removal of cadmium, a function of the human MRP gene. This animal model of MRP function should be useful in further understanding the mechanism of action of this drug and heavy metal transporters.

肿瘤对多种药物的耐药性（Multidrug Resistance，MDR）， 这是癌症化疗的一个主要局限。 在某些肿瘤中，MDR是由于 P-糖蛋白/（PGP）MDR基因的过表达，或 多药耐药相关蛋白（MRP）。 PGP和MRP是成员 三磷酸腺苷（ATP）依赖性转运蛋白家族， 已经显示出导致大量化合物的流出 从细胞。 这个基因家族被称为ATP结合盒 (ABC)家族及其成员运输多种不同的化合物 穿过细胞和组织的膜。 人类ABC基因 与许多疾病有关，包括囊性纤维化， 肾上腺脑白质营养不良和家族性持续性高胰岛素血症 低血糖 鉴定与多药耐药有关的新基因 我们已经鉴定了21个新的人类ABC基因。 基因定位 这些基因中的每一个以及它们的表达模式已经被 测定 这些基因之一，MRP 3，主要表达于 肝脏 该基因在一组细胞中的表达用于 筛选了40，000个潜在的化疗家庭， 评估。 这些数据提供了分子性质的信息 由MRP 3运输。 我们克隆了秀丽隐杆线虫的同源基因 人MRP基因mrp-1的表达 在这个线虫的细胞里。mrp-1基因在几种细胞中表达， 分泌细胞中的动物，符合基因发挥作用， 在去除有毒化合物方面。 mrp-1的遗传破坏 基因表明，它是必不可少的去除镉， 人类MRP基因的功能。 MRP功能的动物模型 应有助于进一步了解的作用机制， 这种药物和重金属转运体