ABCB1 p.Phe978Ser
| Predicted by SNAP2: | A: D (66%), C: N (57%), D: D (91%), E: D (85%), G: D (80%), H: D (80%), I: N (78%), K: D (85%), L: N (66%), M: N (53%), N: D (75%), P: D (91%), Q: D (71%), R: D (85%), S: N (53%), T: D (71%), V: N (61%), W: D (85%), Y: D (66%), |
| Predicted by PROVEAN: | A: D, C: D, D: D, E: D, G: D, H: D, I: D, K: D, L: D, M: D, N: D, P: D, Q: D, R: D, S: D, T: D, V: D, W: D, Y: N, |
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[hide] Chemoprotection of hematopoietic cells by a mutant... Hum Gene Ther. 2000 Mar 1;11(4):555-65. Hafkemeyer P, Licht T, Pastan I, Gottesman MM
Chemoprotection of hematopoietic cells by a mutant P-glycoprotein resistant to a potent chemosensitizer of multidrug-resistant cancers.
Hum Gene Ther. 2000 Mar 1;11(4):555-65., 2000-03-01 [PMID:10724034]
Abstract [show]
Cancers are frequently chemoresistant because of overexpression of P-glycoprotein. Two different approaches to improve cancer treatment are currently being investigated in clinical trials: inhibition of P-glycoprotein function by reversing agents, and alleviation of leukocytopenia by MDR1 gene transfer to normal bone marrow of patients. We report here that retroviral vectors encoding a mutant P-glycoprotein (MDR1-F983A) protect hematopoietic cells from anticancer drugs even in the presence of trans-(E)-flupentixol, an inhibitor of P-glycoprotein. Transfer of either mutant or wild-type MDR1 to K562 erythroleukemia cells or primary murine bone marrow resulted in reduced accumulation of daunomycin and vinblastine because of increased drug efflux.trans-(E)-Flupentixol at concentrations up to 10 microM failed to reverse drug efflux mediated by the product of the mutant MDR1 while wild-type P-glycoprotein was inhibited. In the presence of 2 microM trans-(E)-flupentixol chemoresistance to daunomycin was circumvented only in K562 cells transduced with wild-type, but not with mutant, MDR1. Moreover, drug resistance of KB-8-5 epidermoid cancer cells, which express the wild-type MDR1 gene at levels comparable to clinical specimens from multidrug-resistant cancers, was fully overcome in the presence of trans-(E)-flupentixol. Vectors expressing mutant P-glycoprotein may help improve chemotherapy by allowing safe dose intensification under conditions in which multidrug-resistant cancers are rendered drug sensitive by reversing agents.
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No. Sentence Comment
186 Other mutations in close proximity, e.g., F978A and F978S, affect primarily the drug resistance profile of P-gp (Loo and Clarke, 1993).
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ABCB1 p.Phe978Ser 10724034:186:52
status: NEW[hide] Functional consequences of phenylalanine mutations... J Biol Chem. 1993 Sep 25;268(27):19965-72. Loo TW, Clarke DM
Functional consequences of phenylalanine mutations in the predicted transmembrane domain of P-glycoprotein.
J Biol Chem. 1993 Sep 25;268(27):19965-72., 1993-09-25 [PMID:8104183]
Abstract [show]
Site-directed mutagenesis was used to investigate whether phenylalanine residues in predicted transmembrane sequences play essential roles in the function of human P-glycoprotein. Mutant cDNAs, in which codons for each of the 31 phenylalanine residues were changed to alanine, were expressed in mouse NIH 3T3 cells and analyzed with respect to their ability to confer resistance to various drugs. Mutation of either Phe-335 to Ala in transmembrane segment 6, or Phe-978 to Ala in transmembrane segment 12, drastically altered the drug resistance profile conferred by the mutant P-glycoprotein in transfected cells. Mutant Phe-335-->Ala conferred little resistance to vinblastine or actinomycin D but retained the ability to confer resistance to colchicine and adriamycin. The mutant also showed increased binding of azidopine, which could be inhibited by lower levels of vinblastine, relative to the wild-type enzyme. By contrast, mutant Phe-978-->Ala conferred little or no resistance to colchicine or adriamycin, while its ability to confer resistance to vinblastine or actinomycin D was retained. These results suggest that Phe-335 and Phe-978 play important roles in the recognition and transport of specific substrates by P-glycoprotein. Mutation of Phe-777 to Ala affected the biosynthesis of the transporter. Mutation of the other 28 phenylalanine residues yielded protein products with structural and functional characteristics that were indistinguishable from the wild-type enzyme.
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No. Sentence Comment
120 To test theeffects of other changes to these two residues, site-directed mutagenesis was used to change either Phe-335 or Phe-978 to serine (polar residue), leucine (small non-polar residue),or to tyrosine (aromatic residue withpolar side chain).
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ABCB1 p.Phe978Ser 8104183:120:122
status: NEW126 Mutants with changes of Phe-978 to Ser, Leu, or Tyr all retained the ability to confer resistance to vinblastine, since drug-resistantcolonies were obtained after transfection with the corresponding mutant cDNAs.
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ABCB1 p.Phe978Ser 8104183:126:24
status: NEW127 No colchicine-resistant colonies, however, were observed after transfection of cells with cDNAs coding for mutants Phe-978 Ser or Leu.
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ABCB1 p.Phe978Ser 8104183:127:115
status: NEW