ABC Transporters in Human Disease and Multidrug Resistance

分子进出细胞的运输是最关键的 生物体的功能。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在细胞中至关重要。 肿瘤的抵抗力此外，许多遗传性疾病是由以下缺陷引起的： 转运蛋白ATP结合盒（ABC）基因家族编码转运蛋白 泵送各种化合物穿过细胞和组织的膜。过表达 ABC转运蛋白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。肿瘤干细胞中的ABC基因 基因在癌症干细胞中表达，从而允许对癌症治疗的先天抗性。 ABCG 2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质的新抑制剂。其中一 是一种新的化合物，被称为botrylamides。肉毒酰胺是在海洋中发现的 海绵，化学上足够简单，可以合成衍生物， 确定结构/功能关系。 ABCG 2是一个 肿瘤干细胞中重要标志物和抗性因子。这些化合物中的几种可以是 显示抑制蛋白质的底物结合和/或ATP酶活性。ABCB 5基因， 我们在10年前发现的一种基因被证明是黑色素瘤干细胞的标志物。我们 开发针对这种蛋白质的抗体，并在培养物中表达这种蛋白质， 进一步研究其功能。代谢组学研究ABC基因的功能 ABCC 6基因导致弹性假黄瘤 启动了一项代谢组学研究男性患者的尿液已用于产生代谢物 数据区.我们还开始了血清和尿液的研究， Abcc 6-/-小鼠和来自ABCC缺陷的酵母细胞 亚家族基因这些研究应该有助于我们确定这种转运蛋白的底物。 完整的ABC基因的特点是在海胆，一个主要的模式 生物发展和细胞生物学。动物模型我们发现海胆有一个 药物转运蛋白基因以及许多人类基因的直系同源物的显著扩增的互补物， 疾病基因此外，我们还研究了ABC基因的互补性， 甲壳类水蚤是一种全球分布的有机体， 湖泊和池塘。水蚤不仅是第一种甲壳类动物，也是第一种非昆虫类动物 节肢动物的基因组序列。

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.