Broeks A, Gerrard B, Allikmets R, Dean M, Plasterk R H
Division of Molecular Biology, The Netherlands Cancer Institute, Amsterdam.
EMBO J. 1996 Nov 15;15(22):6132-43.
Acquired resistance of mammalian cells to multiple chemotherapeutic drugs can result from enhanced expression of the multidrug resistance-associated protein (MRP), which belongs to the ABC transporter superfamily. ABC transporters play a role in the protection of organisms against exogenous toxins by cellular detoxification processes. We have identified four MRP homologues in the soil nematode Caenorhabditis elegans, and we have studied one member, mrp-1, in detail. Using an mrp::lacZ gene fusion, mrp-l expression was found in cells of the pharynx, the pharynx-intestinal valve and the anterior intestinal cells, the rectum-intestinal valve and the epithelial cells of the vulva. Targeted inactivation of mrp-l resulted in increased sensitivity to the heavy metal ions cadmium and arsenite, to which wild-type worms are highly tolerant. The most pronounced effect of the mrp-1 mutation is on the ability of animals to recover from temporary exposure to high concentrations of heavy metals. Nematodes were found to be hypersensitive to heavy metals when both the MRP homologue, mrp-1, and a member of the P-glycoprotein (Pgp) gene family, pgp-1, were deleted. We conclude that nematodes have multiple proteins, homologues of mammalian proteins involved in the cellular resistance to chemotherapeutic drugs, that protect them against heavy metals.
哺乳动物细胞对多种化疗药物产生的获得性耐药可能源于多药耐药相关蛋白（MRP）表达的增强，该蛋白属于ABC转运蛋白超家族。ABC转运蛋白通过细胞解毒过程在保护生物体免受外源性毒素侵害方面发挥作用。我们在土壤线虫秀丽隐杆线虫中鉴定出了四种MRP同源物，并对其中一个成员mrp-1进行了详细研究。利用mrp::lacZ基因融合技术，发现mrp-1在咽部细胞、咽-肠瓣膜和前肠细胞、直肠-肠瓣膜以及外阴上皮细胞中表达。mrp-1的靶向失活导致对重金属离子镉和亚砷酸盐的敏感性增加，而野生型线虫对这些重金属具有高度耐受性。mrp-1突变最显著的影响在于动物从短期暴露于高浓度重金属中恢复的能力。当MRP同源物mrp-1和P-糖蛋白（Pgp）基因家族的一个成员pgp-1都缺失时，线虫对重金属变得高度敏感。我们得出结论，线虫拥有多种与哺乳动物中参与细胞对化疗药物耐药性的蛋白质同源的蛋白质，这些蛋白质保护它们免受重金属侵害。
