Targeting the oligomerization of human ABCG2

多药耐药（MDR）是人类肿瘤化疗成功的主要问题。一 癌细胞中MDR的已知机制之一是膜蛋白的表达升高， 介导抗癌药物的外排。具有这种药物外排功能的三种主要膜蛋白 已确定：P-糖蛋白（Pgp），多药耐药相关蛋白1（MRP 1），乳腺癌 癌耐药蛋白/米托蒽醌耐药蛋白（BCRP/MXR）。这些蛋白质属于ATP- 结合盒（ABC）膜转运蛋白超家族，也称为ABCB 1、ABCC 1和ABCC 2。 ABCG 2，分别。我们实验室的长期目标是了解 并克服癌细胞中ABC转运蛋白介导的MDR。 与人ABCB 1和ABCC 1不同，人ABCG 2是一种半ABC转运蛋白，其核苷酸 结合结构域位于氨基末端，并且被认为作为同源二聚体起作用。然而，在这方面， 我们最近的研究表明它以同十二聚体的形式存在。在这个应用程序中，我们计划测试 假设人ABCG 2作为同源十二聚体而不是普遍的同源二聚体起作用， 可以靶向寡聚化过程以逆转ABCG 2介导的耐药性。为此，我们计划 （1）确定人ABCG 2是否是同源二聚体或 （2）确定人ABCG 2的十二聚体形式是否是功能性转运蛋白;（3）确定人ABCG 2的十二聚体形式是否是功能性转运蛋白。 确定人ABCG 2的寡聚化是否发生在内质网（ER）中;（4）确定 人ABCG 2的羧基跨膜结构域是否负责寡聚化;（5）确定 是否有可能通过破坏其寡聚化过程来逆转ABCG 2介导的耐药性。 印第安纳州大学癌症研究所优良的科学环境和慷慨的 机构支持将极大地促进这一项目的成功。信息和 从这项研究中获得的探针将有助于我们了解人类ABCG 2介导的分子机制， 毒品运输这项工作也可能使我们发现一类新的治疗药物， 克服抗药性癌症。

Multidrug resistance (MDR) is a major problem for successful chemotherapy of human cancers. One of the known mechanisms of MDR in cancer cells is the elevated expression of membrane proteins that mediate the efflux of anticancer drugs. Three major membrane proteins that have this drug-efflux function have been identified: P-glycoprotein (Pgp), multidrug resistance-associated proteinl (MRP1), and breast cancer resistance protein/mitoxantrone resistance protein (BCRP/MXR). These proteins belong to the ATP- binding cassette (ABC) membrane transporter superfamily and are also named as ABCB1, ABCC1, and ABCG2, respectively. The long-term goal of our laboratory is to understand the molecular mechanisms of and to overcome ABC transporter-mediated MDR in cancer cells. ' Unlike human ABCB1 and ABCC1, human ABCG2 is a half ABC transporter with its nucleotide binding domain located at the amino terminus and has been thought to function as a homodimer. However, our recent studies suggest that it exists as a homododecamer. In this application, we plan to test the hypothesis that human ABCG2 functions as a homododecamer rather than the prevailing homodimer and we can target the oligomerization process to reverse ABCG2-mediated drug resistance. To this end, we plan to accomplish the following five specific aims: (1) to determine if human ABCG2 is a homodimer or homododecamer; (2) to determine if the dodecameric form of human ABCG2 is a functional transporter; (3) to determine if the oligomerization of human ABCG2 occurs in the endoplasmic reticulum (ER); (4) to determine if the carboxyl transmembrane domain of human ABCG2 is responsible for oligomerization; (5) to determine if it is possible to reverse ABCG2-mediated drug resistance by disrupting its oligomerization process. The excellent scientific environment at Indiana University Cancer Research Institute and the generous institutional support will contribute enormously to the likelihood of success of this project. The information and probes obtained from this study will help us understand the molecular mechanism of human ABCG2-mediated drug transport. This work may also lead us to the discovery of a new class of therapeutic agents that can help overcome drug-resistant cancers.