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Expression of Human MRP6, a Homologue of the Multidrug Resistance Protein Gene MRP1, in Tissues and Cancer Cells¹

Division of Molecular Biology, The Netherlands Cancer Institute, 1066 CX Amsterdam [M. K., M. v. d. L., M. d. H., P. B.], and Department of Neurology, Academic Medical Center, 1105 AZ Amsterdam [F. B.], the Netherlands

The human multidrug resistance protein (MRP) family contains at least six members: MRP1, the gene encoding the multidrug resistance protein; cMOAT or MRP2, encoding the canalicular multispecific organic anion transporter; and four homologues, called MRP3, MRP4, MRP5, and MRP6. The most recently discovered member of the family, MRP6, is analyzed in this report. The MRP6 gene is located on chromosome 16, immediately next to MRP1, and encodes a protein of 1503 amino acids with a predicted molecular weight of M_r 165,000. The 3' end of the MRP6 protein was found to be almost identical with the anthracycline resistance associated (ARA) protein identified previously in epirubicin-selected leukemia cells. Using both 3'- and 5'-derived MRP6 probes, we found that MRP6 is highly expressed in liver and kidney and to a low or very low extent in a few other tissues. No evidence was obtained for an independent expression of the ARA part of the MRP6 gene in normal tissues. To assess a possible role for MRP6 in multidrug resistance, we examined a large panel of resistant cell lines for the (over)expression of MRP6. We found overexpression of the complete MRP6 gene or part of it only in those cell lines with high overexpression and amplification of the MRP1 gene. DNA blot (Southern) analysis showed that MRP6 or a part of it is also amplified in these cell lines. Our results suggest that MRP6 does not play a role in the resistance of the resistant cells analyzed, and that MRP6/ARA is only coamplified with MRP1 because of its location immediately next to it on the same chromosome.

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