ABCC1 p.Glu1089Lys
| Predicted by SNAP2: | A: D (53%), C: D (71%), D: D (66%), F: D (85%), G: D (75%), H: D (85%), I: D (75%), K: D (71%), L: D (75%), M: D (80%), N: D (66%), P: D (85%), Q: D (75%), R: D (85%), S: D (59%), T: D (63%), V: D (71%), W: D (91%), Y: D (85%), |
| Predicted by PROVEAN: | A: N, C: D, D: N, F: D, G: N, H: N, I: D, K: N, L: N, M: N, N: N, P: N, Q: N, R: N, S: N, T: N, V: N, W: D, Y: N, |
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[hide] Identification of an amino acid residue in multidr... J Biol Chem. 2001 Apr 20;276(16):13231-9. Epub 2001 Jan 23. 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 [PMID:11278596]
Abstract [show]
Murine multidrug resistance protein 1 (mrp1), unlike human MRP1, does not confer resistance to anthracyclines. Previously, we have shown that a human/murine hybrid protein containing amino acids 959-1187 of MRP1 can confer resistance to these drugs. We have now examined the functional characteristics of mutant proteins in which we have converted individual amino acids in the comparable region of mrp1 to those present at the respective locations in MRP1. These mutations had no effect on the drug resistance profile conferred by mrp1 with the exception of converting glutamine 1086 to glutamate, as it is in the corresponding position (1089) in MRP1. This mutation created a protein that conferred resistance to doxorubicin without affecting vincristine resistance, or the ability of mrp1 to transport leukotriene C(4) (LTC(4)) and 17beta-estradiol 17-(beta-d-glucuronide) (E(2)17betaG). Furthermore, mutation Q1086D conferred the same phenotype as mutation Q1086E while the mutation Q1086N did not detectably alter the drug resistance profile of mrp1, suggesting that an anionic side chain was required for anthracycline resistance. To confirm the importance of MRP1 E1089 for conferring resistance to anthracyclines, we mutated this residue to Gln, Asp, Ala, Leu, and Lys in the human protein. The mutation E1089D showed the same phenotype as MRP1, while the E1089Q substitution markedly decreased resistance to anthracyclines without affecting LTC(4) and E(2)17betaG transport. 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 LTC(4), E(2)17betaG, and the GSH-dependent substrate, estrone-3-sulfate. These results demonstrate that an acidic amino acid residue at position 1089 in predicted TM14 of MRP1 is critical for the ability of the protein to confer drug resistance particularly to the anthracyclines, but is not essential for its ability to transport conjugated organic anions such as LTC(4) and E(2)17betaG.
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No. Sentence Comment
116 Typical survival curves for transfectants expressing wild type MRP1 and the mutant proteins E1089Q, E1089D, and E1089K are shown in Fig. 4.
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ABCC1 p.Glu1089Lys 11278596:116:112
status: NEW146 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.
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ABCC1 p.Glu1089Lys 11278596:146:266
status: NEW147 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).
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ABCC1 p.Glu1089Lys 11278596:147:89
status: NEW172 However, mutation of glutamate 1089 to lysine completely eliminated resistance to both anthracyclines and vincristine (Table II).
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ABCC1 p.Glu1089Lys 11278596:172:21
status: NEW[hide] Molecular cloning and pharmacological characteriza... Drug Metab Dispos. 2003 Aug;31(8):1016-26. Nunoya K, Grant CE, Zhang D, Cole SP, Deeley RG
Molecular cloning and pharmacological characterization of rat multidrug resistance protein 1 (mrp1).
Drug Metab Dispos. 2003 Aug;31(8):1016-26., [PMID:12867490]
Abstract [show]
Multidrug resistance protein 1 (MRP1) transports a wide range of structurally diverse conjugated and nonconjugated organic anions and some peptides, including oxidized and reduced glutathione (GSH). The protein confers resistance to certain heavy metal oxyanions and a variety of natural product-type chemotherapeutic agents. Elevated levels of MRP1 have been detected in many human tumors, and the protein is a candidate therapeutic target for drug resistance reversing agents. Previously, we have shown that human MRP1 (hMRP1) and murine MRP1 (mMRP1) differ in their substrate specificity despite a high degree of structural conservation. Since rat models are widely used in the drug discovery and development stage, we have cloned and functionally characterized rat MRP1 (rMRP1). Like mMRP1 and in contrast to hMRP1, rMRP1 confers no, or very low, resistance to anthracyclines and transports the two estrogen conjugates, 17beta-estradiol-17-(beta-d-glucuronide) (E217betaG) and estrone 3-sulfate, relatively poorly. Mutational studies combined with vesicle transport assays identified several amino acids conserved between rat and mouse, but not hMRP1, that make major contributions to these differences in substrate specificity. Despite the fact that the rodent proteins transport E217betaG poorly and the GSH-stimulated transport of estrone 3-sulfate is low compared with hMRP1, site-directed mutagenesis studies indicate that different nonconserved amino acids are involved in the low efficiency with which each of the two estrogen conjugates is transported. Our studies also suggest that although rMRP1 and mMRP1 are 95% identical in primary structure, their substrate specificities may be influenced by amino acids that are not conserved between the two rodent proteins.
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301 Previously, we showed that the hMRP1 TM 14 mutations E1089Q and E1089K, which either reduce or completely eliminate resistance to doxorubicin and vincristine, had no effect on estrone 3-sulfate transport (Zhang et al., 2001b).
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ABCC1 p.Glu1089Lys 12867490:301:64
status: NEW[hide] A molecular understanding of ATP-dependent solute ... Cancer Metastasis Rev. 2007 Mar;26(1):15-37. Chang XB
A molecular understanding of ATP-dependent solute transport by multidrug resistance-associated protein MRP1.
Cancer Metastasis Rev. 2007 Mar;26(1):15-37., [PMID:17295059]
Abstract [show]
Over a million new cases of cancers are diagnosed each year in the United States and over half of these patients die from these devastating diseases. Thus, cancers cause a major public health problem in the United States and worldwide. Chemotherapy remains the principal mode to treat many metastatic cancers. However, occurrence of cellular multidrug resistance (MDR) prevents efficient killing of cancer cells, leading to chemotherapeutic treatment failure. Numerous mechanisms of MDR exist in cancer cells, such as intrinsic or acquired MDR. Overexpression of ATP-binding cassette (ABC) drug transporters, such as P-glycoprotein (P-gp or ABCB1), breast cancer resistance protein (BCRP or ABCG2) and/or multidrug resistance-associated protein (MRP1 or ABCC1), confers an acquired MDR due to their capabilities of transporting a broad range of chemically diverse anticancer drugs. In addition to their roles in MDR, there is substantial evidence suggesting that these drug transporters have functions in tissue defense. Basically, these drug transporters are expressed in tissues important for absorption, such as in lung and gut, and for metabolism and elimination, such as in liver and kidney. In addition, these drug transporters play an important role in maintaining the barrier function of many tissues including blood-brain barrier, blood-cerebral spinal fluid barrier, blood-testis barrier and the maternal-fetal barrier. Thus, these ATP-dependent drug transporters play an important role in the absorption, disposition and elimination of the structurally diverse array of the endobiotics and xenobiotics. In this review, the molecular mechanism of ATP-dependent solute transport by MRP1 will be addressed.
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No. Sentence Comment
151 Mutation of E1089K completely eliminated resistance to anthracyclines and vincristine without affecting LTC4 and E217βG transport [81].
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ABCC1 p.Glu1089Lys 17295059:151:12
status: NEW