ABCMdb

ABCG2 p.Asn557Asp

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PMID: 14566825 [PubMed] Miwa M et al: "Single amino acid substitutions in the transmembrane domains of breast cancer resistance protein (BCRP) alter cross resistance patterns in transfectants."

No. Sentence Comment

5 Cells transfected with N557D-BCRP cDNA showed similar resistance to mitoxantrone but lower resistance to SN-38 than the wild-type BCRP-transfected cells. Login to comment
56 PA/N557D showed a similar resistance to mitoxantrone but 5-fold lower resistance to SN-38 than PA/WT1 (Fig. 2c). Login to comment
76 As shown in Figure 3, E446G-, R482G-, N557D- and H630L-BCRP were expressed on the cell surface. Login to comment
84 Estrone is the first physiological substrate that was shown to circumvents BCRP-mediated drug resistance.17 As shown in Table I, estrone effectively reversed mitoxantrone resistance and SN-38 resistance of PA/R482G, PA/R482S, PA/N557H, PA/N557D, PA/H630E and PA/H630L. Login to comment
86 Similarly, fumitremorgin C, a well-known BCRP inhibitor, strongly reversed the mitoxantrone resistance and SN-38 resistance of PA/R482G, PA/R482S, PA/ N557H, PA/N557D, PA/H630E and PA/H630L (Table III). Login to comment
105 PA/N557D cells exhibited similar resistance to mitoxantrone but less resistance to SN-38 than PA/WT1. Login to comment
110 In addition, we constructed N557-mutants because N557D-BCRP isolated by PCR-based mutagenesis was found to have altered cross resistance patterns (unpublished result of the authors). Login to comment
140 TABLE I - REVERSAL OF MITOXANTRONE RESISTANCE AND SN-38 RESISTANCE BY ESTRONE1 Cell line Degree of Mitoxantrone resistance Reversal index Degree of SN-38 resistance Reversal index Control 10 ␮M estrone Control 10 ␮M estrone PA/WT1 7.1 Ϯ 0.6 2.2 Ϯ 0.4 3.2 28 Ϯ 1 4.7 Ϯ 0.3 6.0 PA/R482S 120 Ϯ 20 6.8 Ϯ 0.4 18 37 Ϯ 2 4.4 Ϯ 1.1 8.4 PA/R482G 84 Ϯ 17 3.7 Ϯ 0.3 23 22 Ϯ 1 3.3 Ϯ 0.1 6.7 PA/N557H 3.3 Ϯ 0.1 1.0 Ϯ 0.1 3.3 4.8 Ϯ 0.5 3.4 Ϯ 0.1 1.4 PA/N557D 7.4 Ϯ 0.2 1.4 Ϯ 0.1 5.3 3.8 Ϯ 0.6 2.9 Ϯ 0.2 1.3 PA/H630E 5.8 Ϯ 0.2 1.1 Ϯ 0.1 5.3 20 Ϯ 2.8 6.0 Ϯ 0.1 3.3 PA/H630L 3.3 Ϯ 0.1 0.9 Ϯ 0.1 3.7 8.6 Ϯ 0.4 2.7 Ϯ 0.1 3.2 1 Cells were cultured in the absence or presence of 10 ␮M estrone with increasing concentrations of mitoxantrone or SN-38. Degree of resistance is the ratio of the IC50 value for BCRP-expressing cells divided by that for parental PA317. Login to comment
143 The reversal index is calculated by dividing degree of resistance without estrone by that with estrone. TABLE III - REVERSAL OF MITOXANTRONE RESISTANCE AND SN-38 RESISTANCE BY FUMITREMORGIN C1 Cell line Degree of Mitoxantrone resistance Reversal index Degree of SN-38 resistance Reversal index Control 3 ␮M Fumitremorgin C Control 3 ␮M Fumitremorgin C PA/WT1 11 Ϯ 1 1.0 Ϯ 0.1 11 23 Ϯ 1 1.1 Ϯ 0.1 21 PA/R482S 140 Ϯ 10 1.2 Ϯ 0.1 120 41 Ϯ 1 0.9 Ϯ 0.1 46 PA/R482G 89 Ϯ 21 0.9 Ϯ 0.1 99 17 Ϯ 2 0.9 Ϯ 0.1 19 PA/N557H 3.3 Ϯ 0.1 1.0 Ϯ 0.1 3.3 4.8 Ϯ 0.5 1.1 Ϯ 0.1 4.4 PA/N557D 7.4 Ϯ 0.2 0.8 Ϯ 0.0 9.3 3.8 Ϯ 0.6 1.2 Ϯ 0.1 3.2 PA/H630E 5.8 Ϯ 0.2 1.1 Ϯ 0.1 5.3 20 Ϯ 2.8 1.4 Ϯ 0.1 14 PA/H630L 3.3 Ϯ 0.1 0.9 Ϯ 0.1 3.7 8.6 Ϯ 0.4 1.4 Ϯ 0.1 6.1 1 These cells were cultured in the absence or presence of 3 ␮M fumitremorgin C with increasing concentrations of mitoxantrone or SN-38. Degree of resistance is the ratio of IC50 value for BCRP-expressing cells divided by that for parental PA317. Login to comment

PMID: 15875186 [PubMed] Mohrmann K et al: "Absence of N-linked glycosylation does not affect plasma membrane localization of breast cancer resistance protein (BCRP/ABCG2)."

No. Sentence Comment

170 The described difference in resistance of the BCRP-N557H, BCRP-N557D, BCRP-N557E and BCRP-N557R mutants could be partially due to a small difference in folding of BCRP next to a difference in affinity. Login to comment

PMID: 16108826 [PubMed] Sugimoto Y et al: "Breast cancer resistance protein: molecular target for anticancer drug resistance and pharmacokinetics/pharmacodynamics."

No. Sentence Comment

62 Cells transfected with N557D-BCRP cDNA showed a similar level of resistance to mitoxantrone, but lower resistance to SN-38 than wild-type BCRP-transfected cells. Login to comment

PMID: 16146333 [PubMed] Mao Q et al: "Role of the breast cancer resistance protein (ABCG2) in drug transport."

No. Sentence Comment

153 transfected with mutant BCRP cDNA with substitution of Asn residue at position 557 to Asp (N557D) exhibited comparable resistance to mitoxantrone but significantly reduced resistance to SN-38 relative to wild-type protein. Login to comment

PMID: 16842198 [PubMed] Perez-Tomas R et al: "Multidrug resistance: retrospect and prospects in anti-cancer drug treatment."

No. Sentence Comment

211 Cells transfected with N557D showed a similar level of resistance to mitoxantrone, but lower resistance to SN-38 than did wild-type BCRP-transfected cells. Login to comment

PMID: 17027309 [PubMed] Li YF et al: "Towards understanding the mechanism of action of the multidrug resistance-linked half-ABC transporter ABCG2: a molecular modeling study."

No. Sentence Comment

182 In sf9 cell, it is expressed on cell surface, but with no ATPase activity [56] L554P TM5 Lowered drug resistance [42] N557D,E TM5 Functional [21] S566Aa ECL (between TM5 and 6) Lowered drug resistance for the cell line [42] N596Q Between TM5 and 6 N-glycosylation site [65] Y605Ca Loop between TM5 and 6 Lowered drug resistance for the cell line [42] D620N Loop between TM5 and 6 SNP polymorphism [22] H630E,L TM6 Functional [21] A632Va TM Lowered drug resistance for the cell line [42] a Mutants not well characterized. Login to comment

PMID: 17569216 [PubMed] Limtrakul P et al: "Curcumin as chemosensitizer."

No. Sentence Comment

82 Cells transfected with mutant ABCG2 cDNA with substitution of Asn residue at position 557 to Asp (N557D) exhibited comparable resistance to mitoxantrone but significantly reduced resistance to SN-38 relative to wild-type protein. Position 557 is predicted to be located within or proximal to the TM5 segment. Login to comment

PMID: 18249138 [PubMed] Hazai E et al: "Homology modeling of breast cancer resistance protein (ABCG2)."

No. Sentence Comment

245 However, in our model, R482 cannot form interaction with rhodamine, but L484 is in interacting distance Table 3 Mutations on BCRP and their effect on its function Mutation Effect/results Reference V12M Did not effect Hemato and MTX transport Tamura et al. (2006) G51C Did not effect Hemato and MTX transport Tamura et al. (2006) K86M Inactivates transporter (dominant negative effect on ATPase activity); alters subcellular distribution Henriksen et al. (2005a) K86M Transporter inactive, but still able to bind ATP Ozvegy et al. (2002) Q126stop Defective porphyrin transport Tamura et al. (2006) Q141K Did not effect Hemato and MTX transport Tamura et al. (2006) T153M Did not effect Hemato and MTX transport Tamura et al. (2006) Q166E Did not effect Hemato and MTX transport Tamura et al. (2006) I206L Did not effect Hemato and MTX transport Tamura et al. (2006) F208S Defective porphyrin transport Tamura et al. (2006) S248P Defective porphyrin transport Tamura et al. (2006) E334stop Defective porphyrin transport Tamura et al. (2006) F431L Effects MTX transport Tamura et al. (2006) S441N Defective porphyrin transport Tamura et al. (2006) E446-mutants No drug resistance Miwa et al. (2003) R482G, R482T Effects MTX transport Tamura et al. (2006) R482T Substrate drug transport and inhibitor efficiency is not mediated by changes in drug-binding Pozza et al. (2006) R482G, R482T Substitution influence the substrate specificity of the transporter Ozvegy et al. (2002) R482G, R482T Altered substrate specificity Honjo et al. (2001) R482G Methotrexate not transported Chen et al. (2003b) Mitomo et al. (2003) R482G Resistance to hydrophilic antifolates in vitro, G482-ABCG2 mutation confers high-level resistance to various hydrophilic antifolates Shafran et al., (2005) R482G Three distinct drug, binding sites Clark et al. (2006) R482G Altered substrate specificity, granulocyte maturation uneffected Ujhelly et al. (2003) R482 mutants Higher resistance to mitoxantrone and doxorubicin than wt Miwa et al. (2003) R482X Affects substrate transport and ATP hydrolysis but not substrate binding Ejendal et al. (2006) F489L Impaired porphyrin transport Tamura et al. (2006) G553L; G553E Impaired trafficing, expression, and N-linked glycosylation Polgar et al. (2006) L554P Dominant negative effect on drug sensitivity Kage et al. (2002) N557D Resistance to MTX, but decreased transport of SN-38; N557E no change in transport compared to wt Miwa et al. (2003) F571I Did not effect Hemato and MTX transport Tamura et al. (2006) N590Y Did not effect Hemato and MTX transport Tamura et al. (2006) C592A Impaired function and expression Henriksen et al. (2005b) C592A/C608A Restored plasma mb expression; MTX transport normal, BODIPY-prazosin impaired Henriksen et al. (2005b) C603A Disulfide bridge; no functional or membrane targeting change Henriksen et al. (2005b) C608A Impaired function and expression Henriksen et al. (2005b) D620N Did not effect Hemato and MTX transport Tamura et al. (2006) H630X No change in transport Miwa et al. (2003) Cand N-terminal truncated Impaired trafficing Takada et al. (2005) with the ligand. Login to comment

PMID: 19111841 [PubMed] Noguchi K et al: "Functions of the breast cancer resistance protein (BCRP/ABCG2) in chemotherapy."

No. Sentence Comment

839 Cells expressing either the N557D or the H630E BCRP mutant displayed a lower resistance to SN-38, although the mitoxantrone-resistance of these cells was comparable to that observed for the wild-type BCRP-expressing cells. Login to comment