ABC Transporters in Human Disease and Multidrug Resistance

ATP结合盒（ABC）基因家族编码一组不同的转运蛋白，这些转运蛋白将各种化合物泵送穿过细胞和组织的膜。几种人ABC转运蛋白在对化疗药物有抗性的肿瘤细胞中过表达。此外，一些ABC基因（CFTR，SUR，ALDP）在遗传性疾病中发生突变。DCS科学家先前的工作表明，MXR/ABCP基因在对米托蒽醌、拓扑替康和其他几种药物耐药的肿瘤细胞系中过表达。 我们现在已经证明，该基因在胎盘的滋养层细胞中表达，并可能在物质进出胎儿的运输中发挥作用。来自人类基因组的额外表达序列的表征表明存在至少55个ABC基因。 这些基因之一ABCG 5只在肝脏中表达，并在固醇转运障碍中突变。我们还证明了ABCA 1基因是导致丹吉尔病（一种胆固醇转运障碍）的基因。 这两个发现将为胆固醇如何被肠道吸收，从外周组织转运和排泄提供相当大的见解。初步数据表明，其他ABC基因可能与顺铂耐药有关。

The ATP-binding cassette (ABC) gene family encodes a diverse group of transporter proteins that pump a wide variety of compounds across the membranes of cells and tissues. Several human ABC transporters are overexpressed in tumor cells that are resistant to chemotherapy drugs. In addition, several ABC genes ( CFTR , SUR , ALDP ) are mutated in inherited diseases. Previous work with DCS scientists showed that the MXR/ABCP gene is overexpressed in tumor cell lines that are resistant to mitoxantrone, topotecan and several other drugs. We have now shown that the gene is expressed in the trophoblast cells of the placenta and may play a role in transport of substances into or out of the fetus. Characterization of additional expressed sequences from the human genome demonstrates that there are at least 55 ABC genes. One of these genes ABCG5 is expressed exclusively in the liver and is mutated in a sterol transport disorder. We also demonstrated that the ABCA1 gene is the gene responsible for Tangier disease, a disorder of cholesterol transport. Together these two findings will provide considerable insight into how cholesterol is absorbed by the intestine, transported from peripheral tissues, and excreted. Preliminary data suggests that other ABC genes my be involved in cis-platinum resistance.