Targeting the oligomerization of human ABCG2

描述（由申请人提供）：多药耐药（MDR）是人类癌症成功化疗的主要问题。癌细胞中MDR的已知机制之一是介导抗癌药物外排的膜蛋白的表达升高。具有这种药物外排功能的三种主要膜蛋白已被鉴定：P-糖蛋白（Pgp）、多药耐药相关蛋白1（MRP 1）和乳腺癌耐药蛋白/米托蒽醌耐药蛋白（BCRP/MXR）。这些蛋白属于ATP结合盒（ABC）膜转运蛋白超家族，并且也分别被命名为ABCB 1、ABCC 1和ABCG 2。我们实验室的长期目标是了解ABC转运蛋白介导的肿瘤细胞MDR的分子机制，并克服这种机制。 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，并被认为具有同源二聚体的功能。然而，我们最近的研究表明，它是以同十二聚体的形式存在的。在本申请中，我们计划测试人ABCG 2作为同源十二聚体而不是普遍的同源二聚体起作用的假设，并且我们可以靶向寡聚化过程以逆转ABCG 2介导的耐药性。为此，我们计划完成以下五个具体目标：（1）确定人ABCG 2是否是同源二聚体或同源十二聚体;（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的寡聚化是否发生在内质网（ER）中;（4）确定人ABCG 2的寡聚化是否发生在内质网（ER）中;（5）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的良好科学环境和慷慨的机构支持将极大地促进该项目成功的可能性。本研究所获得的信息和探针将有助于我们了解人ABCG 2介导的药物转运的分子机制。这项工作也可能导致我们发现一类新的治疗药物，可以帮助克服耐药性癌症。

DESCRIPTION (provided by applicant): 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 protein 1 (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.