ABCMdb

ABCB1 p.Ser532Arg

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Publications

PMID: 15212152 [PubMed] Pauli-Magnus C et al: "Functional implications of genetic polymorphisms in the multidrug resistance gene MDR1 (ABCB1)."

No. Sentence Comment

118 Functional Impact in vitro of MDR1 Variants Amino acid change Functional effect of the variant allele Reference Val185Ser Increased colchicine resistance [30] ⌬Phe335 Decreased resistance to vinca alkaloids; no resistance to dactinomycin [31] Lys536Gln, Gly534Asp, Lys536Arg, Ser532Arg, ⌬Tyr490 Defective RNA processing [33] Ala893Ser Acquired overexpression of one allele in drug-resistant cells [20] Ala893Ser Decreased digoxin efflux [19] Asn21Asp, Phe103Leu, Ser400Ala, Ala893Ser, Ala893Thr No effect on P-glycoprotein cell surface expression and substrate specificity [69] Ala893Ser No difference in calcein-AM transport [27] Ala893Ser/Thr No difference in transport of verapamil, digoxin, viblastine and cyclosporine A [35] 3435 polymorphisms were analyzed separately, with AUC values being highest for individuals carrying the reference alleles. Login to comment

PMID: 7914197 [PubMed] Hoof T et al: "Cystic fibrosis-type mutational analysis in the ATP-binding cassette transporter signature of human P-glycoprotein MDR1."

No. Sentence Comment

26 20575 CF-type Mutations in MDRl TABLEI Oligonucleotides used in RTIPCR assays, mutagenesis,and sequencing Sequence Primer' Applicationb 5'-GAGGTGAAGAAGGGCCAGACG-3' mdrlP3175s* P 5'-TTCTGGATGGTGGACAGGCGGTGA-3' mdrlP3716a*P 5'-GTGCAGAGTGGGCAGACGGTG-3' mdrl-1249s 5'-TTACGAACTGTAGACAAACGATGAG-3' 5'-GAGGAGCAGCTTATG-3' 5'-GTGGTTCAGGTGGCT-3' mdrl-1702s S 5'-GAAAACATTCGCTATGGCCGTGAAAATG-3' mdrl-1456s S 5'-GCAGCTGATGAATCC-3' mdrl-1918s S 5"GTGGTGGGCAGgaCAGAGGATCGC-3' mdrl-1595sM (K536Q) 5'-GTTGAGTGGTGuCAGAAGCAGAG-3' mdrl-1590sM (G534D) 5'-GTGGTGGGCAGwCAGAGGATCGC-3' mdrl-1595sM (K536R) 5"CCAGTTGAGGGGTGGGCAG-3' mdrl-1587sM(S532R) 5'-GAAAACATTCGsGCCGTGAAAATG-3' mdrl-1486sM (AY490) 5'-GGCAAGGGCATCCTGGCTGCAGA-3' alh79s* P 5'-TAACGGGCCAGAACATTGGCATT-3' alh521a* P p, s p, s S mdrl-1781a mdrl-1076s The number indicates the positionof the first primer nucleotide in thecorresponding EMBL file cDNA sequences of rabbit aldolase A (ald), human MDRl (mdrl),or CHOMDRl (mdrlc);s, sense direction; a, antisense direction tocDNA sequence. Login to comment
90 The localization ofAY490, S532R, G534D, K536R, K536Q, and AY490-K536Q in the N-terminal half of MDRl is shown in Fig. 1. Login to comment
110 MRK16 recognizes external epitopes of human MDRl without cross-reactions with rodent P-glycoproteins (Hamada and Tsuruo, 1991).The AY490 and AY490-K536Q transfectants were negative for MRK16 like the parentcontrol line CHO K1 (Fig. 4A).In the S532R and G534D MDRls recombinant cell lines, mixed populations of MRK16 immunoreactive cells were observed (Fig. 4A).Subsequentexposure to colchicine(100,125, 150,or 175ng/ml) increased the proportion of cells with higher antigen density with increasing colchicine concentration (Fig. 4B). Login to comment
111 However, the MRK16 signals on these cells were still 15-fold (S532R) or &fold (G534D)lower than in the K1clone that had been transfected with MDRls wild-type sequence (Table11). Login to comment
116 1 , ', k. ,-I wt S532R K536R AY490 I K536Q transcripts in recombinant CHO K1 cells by RTPCR kinetics. Login to comment
123 MDRlcell lines with low (S532R, G534D) or no expression of human P- log Fluorescence Intensity ( 3 Decades) B S532R G534D log Fluorescence Intensity ( 3 Decades ) FIG.4. Login to comment
128 B, FACS analysis of the S532R and G534D MDRls mutant cell lines TABLEI1 Cell surface expression of human P-glycoprotein inMDRls recombinant CHO K1 cells 5 x lo5freshly trypsinized cells in the exponential phase of growth were incubated with 3 pg of anti-human-MDR1 monoclonal antibody MRK16 and then with fluorescein isothiocyanate-labeled rabbit anti-mouse I&. Immunofluorescence of cells was recorded on a FACS. Login to comment
130 Cell line Fluorescence Signalnormalized to CHO K1 control CHO K1 8.6 x 10' CHO K1 (MDR1) 1.0 CHO K1 (AY490 MDR1) 6.3 x 10' 0.7 CHO K1 (S532R MDR1)" 4.4 x 104 51 CHO K1 (G534D MDR1)" 2.1 x 105 240 CHO K1 (K536R MDR1) 5.6 x 105 650 CHO K1 (K536Q MDR1) 9.4 x 105 CHO K1 (AY490-K536QMDR1) 2.1 x lo3 1,100 6.5 x 105 750 2.4 a The datarefer to the MRK16-positive subpopulation. Login to comment
147 Opentriangles, wild-type MDRls CHO K1; closed cycles, K536R MDRls K1; closed triangles, K536Q MDRls K1; stars, S532R MDRls K1; opencircles, AY490 MDRls K1; closed squares, G534D MDRls K1; bars, AY490-K536QMDRls K1; open squares,CHO K1. Login to comment
165 Forthe MDRl system, thecorresponding mutations S532R and G534D conferred only a subtle increase of multidrugresistanceto CHO K1 cells with low amounts of S532R MDRl and G534D MDRl being expressed on the surface of the recombinant host cell. Login to comment

PMID: 9169612 [PubMed] Bakos E et al: "Characterization of the human multidrug resistance protein containing mutations in the ATP-binding cassette signature region."

No. Sentence Comment

25 They found that the MDR1 mutants containing a Ser Arg (S532R) or a Gly Asp (G534D) substitution were present at very low levels in the plasma membrane, and thus did not confer drug resistance. Login to comment

PMID: 16352426 [PubMed] Ambudkar SV et al: "The power of the pump: mechanisms of action of P-glycoprotein (ABCB1)."

No. Sentence Comment

52 Between the Walker A and B sequences is found a linker peptide with the sequence LSGGQ, also known as the C-region or ABC signature sequence, as it is the hallmark of Table 1 - Summary of mutational analysis of conserved residues in nucleotide-binding domains of Pgp Domain Source Residue number Function Reference NBD1 NBD2 A-loop Human Y401A Y1044A No ATP binding/hydrolysis Kim et al. (submitted for publication) Walker A Mouse K429N K1072N Normal ATP binding but no hydrolysis Azzaria et al. (1989) G431A G1073A Human C431 C1074 ATP protects from modification by N-ethylmaleimide Loo and Clarke (1995) Disulfide bond formation between Walker A domains of both NBDs Urbatsch et al. (2001) Human K433M K1076M Decreased ATP-binding Muller et al. (1996) No ATP hydrolysis Szakacs et al. (2000) No vanadate-trapping, but aluminum and beryllium fluoride-induced trapping normal Q-loop Mouse Q471 Q1114 Not essential for ATP hydrolysis but may be involved in communication with drug-substrate sites Urbatsch et al. (2000a) LSGGQ or linker peptide or signature motif Mouse S528A S1173A Normal ATP binding but no hydrolysis Tombline et al. (2004a) Human S532R Decreased cell surface expression Hoof et al. (1994) Human G534C G1179C No ATP hydrolysis Loo et al. (2002) Human G534D Decreased cell surface expression Hoof et al. (1994) No drug resistance Normal cell surface expression Bakos et al. (1997) No ATP hydrolysis Human G534D/V G1179D Interdomain communication Szakacs et al. (2001) Human Q535C Q1180C No ATP hydrolysis Loo et al. (2002) Human K536Q Decreased drug resistance Hoof et al. (1994) LSGGQ or linker peptide or signature motif Human K536R Increased colchicine resistance (normal ATP hydrolysis?) Login to comment