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J. Biol. Chem., Vol. 282, Issue 12, 8821-8830, March 23, 2007

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Regulation of Function by Dimerization through the Amino-terminal Membrane-spanning Domain of Human ABCC1/MRP1^*

From the Department of Pharmacology and Toxicology, Indiana University Cancer Center, and the Walther Oncology Center/Walther Cancer Institute, Indiana University School of Medicine, Indianapolis, Indiana 46202

Overexpression of some ATP-binding cassette (ABC) membrane transporters such as ABCB1/P-glycoprotein/MDR1 and ABCC1/MRP1 causes multidrug resistance in cancer chemotherapy. It has been thought that half-ABC transporters with one nucleotide-binding domain and one membrane-spanning domain (MSD) likely work as dimers, whereas full-length transporters with two nucleotide-binding domains and two or three MSDs function as monomers. In this study, we examined the oligomeric status of the human full-length ABC transporter ABCC1/MRP1 using several biochemical approaches. We found 1) that it is a homodimer, 2) that the dimerization domain is located in the amino-terminal MSD0L0 (where L0 is loop 0) region, and 3) that MSD0L0 has a dominant-negative function when coexpressed with wild-type ABCC1/MRP1. These findings suggest that ABCC1/MRP1 may exist and function as a dimer and that MSD0L0 likely plays some structural and regulatory functions. It is also tempting to propose that the MSD0L0-mediated dimerization may be targeted for therapeutic development to sensitize ABCC1/MRP1-mediated drug resistance in cancer chemotherapy.

Received for publication, January 5, 2007

^* This work was supported in part by National Institutes of Health Grants CA94961 and CA120221 and United States Department of Defense Grant W81XWH-05-1-0102. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Supported in part by National Research Service Award T32 HL07910 from the National Institutes of Health.

² Supported in part by National Research Service Award T32 DK07519 from the National Institutes of Health.

³ Recipient of United States Department of Defense Predoctoral Traineeship W81XWH-04-1-0359.

⁴ Present address: Inst. of Clinical Pharmacology, Central South University Xiangya School of Medicine, Changsha 410078, China.

⁵ To whom correspondence should be addressed: Dept. of Pharmacology and Toxicology, Indiana University Cancer Center, Indiana University School of Medicine, 1044 W. Walnut St., R4–166, Indianapolis, IN 46202. Tel.: 317-278-4503; Fax: 317-274-8046; E-mail: jianzhan{at}iupui.edu.

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