ABC Transporters in Human Disease and Multidrug Resistance

分子进出细胞的运输是生物体最重要的功能之一。在许多情况下，化疗失败的一个重要原因是耐药性。从细胞中清除毒素的泵对肿瘤的抵抗力至关重要。此外，许多遗传疾病是由转运蛋白缺陷引起的。atp结合盒（ABC）基因家族编码转运蛋白，将各种化合物输送到细胞和组织的膜上。ABC转运蛋白的过度表达是化疗药物多药耐药的重要原因，这些基因在多种人类疾病中发生突变。癌症干细胞中的ABC基因在癌症干细胞中表达的几个ABC基因允许对癌症治疗的先天抵抗。ABCG2是一种重要的耐药基因，我们已经筛选并鉴定了该基因编码蛋白的新抑制剂。其中一种是一类新的化合物，被称为botrylamides。botrylamides存在于海洋海绵中，其化学性质简单，可以合成衍生物并确定其结构/功能关系。ABCG2是肿瘤干细胞中重要的标志物和耐药因子。这些化合物中的一些可以被证明抑制底物结合和/或atp酶活性的蛋白质。ABCB5基因，我们在十多年前发现的，已经被证明是黑色素瘤干细胞的标志。我们正在开发针对该蛋白的抗体，并在培养中表达该蛋白，以进一步研究其功能。代谢组学研究ABC基因功能为了解ABCC6基因引起弹性假黄瘤的功能，我们开展了代谢组学研究。男性患者的尿液已被用于生成代谢物谱。我们还启动了Abcc6 -/-小鼠和ABCC亚家族基因缺失酵母细胞的血清和尿液研究。这些研究将有助于我们确定这种转运体的底物。海胆是一种重要的发育和细胞生物学模式生物，在海胆中发现了ABC基因的完整补体。动物模型我们发现海胆具有显著扩展的药物转运基因补体以及许多人类疾病基因的同源物。此外，我们还描述了浮游甲壳类水蚤的ABC基因的补充，水蚤是一种全球分布的生物，对湖泊和池塘的生态至关重要。水蚤不仅是第一个甲壳类动物，也是第一个确定其基因组序列的非昆虫节肢动物。

The transport of molecules into and out of the cell is one of the most critical functions of living organisms. A large reason for the failure of chemotherapy in many cases is drug resistance. Pumps that remove toxins from cells are critically important in the resistance of tumors. In addition a number of genetic diseases are caused by defects in transport proteins. The ATP-binding cassette (ABC) gene family codes for transporter proteins pumping a variety of compounds across the membranes of cells and tissues. Overexpression of ABC transporters is an important cause of multidrug resistance to chemotherapy agents and these genes are mutated in diverse human diseases. ABC genes in cancer stem cells Several ABC genes are expressed in cancer stem cells allowing for an innate resistance to cancer therapy. ABCG2 is an important drug resistance gene and we have screened for and identified new inhibitors to the protein encoded by this gene. One of these is a new class of compounds known as botrylamides. The botrylamides are found in marine sponges and are simple enough chemically that derivatives can be synthesized and a structure/function relationship determined. ABCG2 is an important marker and resistance factor in cancer stem cells. Several of these compounds can be shown to inhibit substrate binding and/or ATPase activity of the protein. The ABCB5 gene, that we identified over 10 years ago has been shown to be a marker for melanoma stem cells. We are developing antibodies against this protein and are expressing the protein in culture to further study its function. Metabolomics to study ABC gene Function To understand the function of the ABCC6 gene causing pseudoxanthoma elasticum we have initiated a metabolomics study. Urine from male patients has been used to generate metabolite profiles. We have also initiated studies of serum and urine from Abcc6 -/- mice and from yeast cell deficient in an ABCC subfamily gene. These studies should aid us in identifying the substrate of this transporter. The complete complement of ABC genes was characterized in the sea urchin, a major model organism for development and cell biology. Animal models We find that the sea urchin has a dramatically expanded complement of drug transporter genes as well as orthologs of many human disease genes. In addition we have characterized the complement of ABC genes in the planktic crustacean Daphnia a globally distributed organism of central importance for the ecology of lakes and ponds. Daphnia is not only the first crustacean, but also the first non-insect arthropod to have its genome sequence determined.