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.
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