ABC Transporters in Human Disease and Multidrug Resistance

分子进出细胞的运输是生物体最关键的功能之一。在许多情况下，化疗失败的一大原因是耐药性。从细胞中清除毒素的泵在肿瘤的抗药性中至关重要。此外，许多遗传性疾病是由运输蛋白缺陷引起的。三磷酸腺苷结合盒(ABC)基因家族编码转运蛋白将各种化合物泵送到细胞和组织的膜上。ABC转运蛋白的过度表达是导致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基因几个ABC基因在癌症干细胞中表达，允许对癌症治疗产生天生的抵抗力。ABCG2是一个重要的耐药基因，我们已经筛选并鉴定了该基因编码的蛋白的新的抑制剂。其中之一是一类新的化合物，被称为波三酰胺。波三酰胺类化合物存在于海绵中，其化学结构非常简单，可以合成衍生物并确定其结构/功能关系。ABCG2是肿瘤干细胞的重要标志物和耐药因子。这些化合物中的几个可以抑制底物结合和/或蛋白质的ATPase活性。我们在10多年前发现的ABCB5基因已被证明是黑色素瘤干细胞的标志。我们正在开发针对这种蛋白的抗体，并在培养中表达这种蛋白，以进一步研究其功能。代谢组学为了研究ABC基因的功能为了了解引起弹性假性黄色瘤的ABCC6基因的功能，我们启动了一项代谢组学研究。男性患者的尿液已被用来生成代谢物图谱。我们还开始了对Abcc6-/-小鼠和ABCC亚家族基因缺陷酵母细胞的血清和尿液的研究。这些研究应该有助于我们确定这种转运蛋白的底物。ABC基因的完整补充是海胆的特征，海胆是发育和细胞生物学的主要模式生物。动物模型我们发现，海胆的药物转运蛋白基因以及许多人类疾病基因的同源基因大大增加。此外，我们还研究了浮游甲壳动物水蚤的ABC基因的互补情况。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.