Homologues of the human multidrug resistance genes MRP and MDR contribute to heavy metal resistance in the soil nematode Caenorhabditis elegans.
Acquired resistance of mammalian cells to multiple chemotherapeutic drugs can result from enhanced expression of the multidrug resistance-associated protein (MRP), which belongs to the ABC transporter superfamily. ABC transporters play a role in the protection of organisms against exogenous toxins by cellular detoxification processes. We have identified four MRP homologues in the soil nematode Caenorhabditis elegans, and we have studied one member, mrp-1, in detail. Using an mrp::lacZ gene fusion, mrp-l expression was found in cells of the pharynx, the pharynx-intestinal valve and the anterior intestinal cells, the rectum-intestinal valve and the epithelial cells of the vulva. Targeted inactivation of mrp-l resulted in increased sensitivity to the heavy metal ions cadmium and arsenite, to which wild-type worms are highly tolerant. The most pronounced effect of the mrp-1 mutation is on the ability of animals to recover from temporary exposure to high concentrations of heavy metals. Nematodes were found to be hypersensitive to heavy metals when both the MRP homologue, mrp-1, and a member of the P-glycoprotein (Pgp) gene family, pgp-1, were deleted. We conclude that nematodes have multiple proteins, homologues of mammalian proteins involved in the cellular resistance to chemotherapeutic drugs, that protect them against heavy metals.
Broeks
A
A
Division of Molecular Biology, The Netherlands Cancer Institute, Amsterdam.
Gerrard
B
B
Allikmets
R
R
Dean
M
M
Plasterk
R H
RH
D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D000595:Amino Acid Sequence; D000818:Animals; D018053:Arsenites / Q000494:pharmacology; D002104:Cadmium / Q000494:pharmacology; D017173:Caenorhabditis elegans / Q000378:metabolism*; D003001:Cloning, Molecular; D018432:Drug Resistance, Multiple / Q000235:genetics*; D019450:Genes, MDR / Q000235:genetics*; D006801:Humans; D019216:Metals, Heavy / Q000494:pharmacology*; D008969:Molecular Sequence Data; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D016415:Sequence Alignment; D017421:Sequence Analysis; D017670:Sodium Compounds / Q000494:pharmacology; D013194:Staining and Labeling; D001616:beta-Galactosidase / Q000378:metabolism
D018528:ATP-Binding Cassette Transporters; D018053:Arsenites; D002104:Cadmium; D019216:Metals, Heavy; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D012333:RNA, Messenger; D011993:Recombinant Fusion Proteins; D017670:Sodium Compounds; D001616:beta-Galactosidase; C017947:sodium arsenite