ABCMdb

PMID: 11278596

Zhang DW, Cole SP, Deeley RG
Identification of an amino acid residue in multidrug resistance protein 1 critical for conferring resistance to anthracyclines.
J Biol Chem. 2001 Apr 20;276(16):13231-9. Epub 2001 Jan 23., 2001-04-20 [PubMed]

Sentences

No. Mutations Sentence Comment

7 ABCC1 p.Glu1089Gln ABCC1 p.Glu1089Asp The mutation E1089D showed the same phenotype as MRP1, while the E1089Q substitution markedly decreased resistance to anthracyclines without affecting LTC4 and E217betaG transport. Login to comment 8 ABCC1 p.Glu1089Ala ABCC1 p.Glu1089Asn ABCC1 p.Glu1089Leu Conversion of Glu-1089 to Asn, Ala, or Leu had a similar effect on resistance to anthracyclines, while conversion to a positive amino acid, Lys, completely eliminated resistance to anthracyclines and vincristine without affecting transport of LTC4, E217betaG, and the GSH-dependent substrate, estrone-3-sulfate. Login to comment 110 ABCC1 p.Glu1089Asp Thus, glutamate 1089 was mutated to aspartate, glutamine, alanine, leucine, and lysine and chemosensitivity assays were carried out. Login to comment 112 ABCC1 p.Glu1089Gln In contrast, conversion of glutamate 1089 to glutamine, as it is in the murine protein, essentially eliminated the ability of MRP1 to confer resistance to doxorubicin, daunorubicin, and epirubicin, as did mutations MRP1E1089A, MRP1E1089L, and MRP1E1089K (Table II). Login to comment 113 ABCC1 p.Glu1089Gln ABCC1 p.Glu1089Ala In addition, mutation of glutamate 1089 to glutamine, alanine, and leucine decreased the relative resistance to vincristine by 55-65%, while mutation to lysine essentially eliminated resistance to this drug. Login to comment 116 ABCC1 p.Glu1089Gln ABCC1 p.Glu1089Asp ABCC1 p.Glu1089Lys Typical survival curves for transfectants expressing wild type MRP1 and the mutant proteins E1089Q, E1089D, and E1089K are shown in Fig. 4. Login to comment 146 ABCC1 p.Glu1089Gln ABCC1 p.Glu1089Asp ABCC1 p.Glu1089Lys In view of the effect of mutations of glutamate 1089 in the human protein on resistance to vincristine and VP-16 in addition to the anthracyclines, we also examined LTC4 and E217betaG transport by wild type and mutant human MRP1, including MRP1, E1089Q, E1089D, and E1089K. Login to comment 147 ABCC1 p.Glu1089Lys However, none of these mutations had any detectable influence on transport including the E1089K mutation that significantly decreased resistance to all drugs tested (Fig. 6, B and D). Login to comment 172 ABCC1 p.Glu1089Lys However, mutation of glutamate 1089 to lysine completely eliminated resistance to both anthracyclines and vincristine (Table II). Login to comment 223 ABCC1 p.Glu1089Gln Mutation of glutamate 1089 to glutamine essentially eliminated anthracycline resistance, confirming the crucial role of this residue. Login to comment 231 ABCC1 p.Glu1089Asp This was supported by the results obtained by substitution of glutamate 1089 with aspartate, which resulted in no detectable change in resistance profile, and by conversion to lysine, which essentially eliminated resistance to both anthracyclines and vincristine, and substantially decreased resistance to VP-16. Login to comment