ABCG2 p.His630Glu
| Predicted by SNAP2: | A: N (61%), C: N (61%), D: N (53%), E: N (61%), F: N (66%), G: N (66%), I: N (78%), K: N (57%), L: N (72%), M: N (72%), N: N (66%), P: D (53%), Q: N (78%), R: N (57%), S: N (72%), T: N (72%), V: N (78%), W: D (53%), Y: N (78%), |
| Predicted by PROVEAN: | A: D, C: D, D: D, E: D, F: D, G: 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: D, |
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[hide] Single amino acid substitutions in the transmembra... Int J Cancer. 2003 Dec 10;107(5):757-63. Miwa M, Tsukahara S, Ishikawa E, Asada S, Imai Y, Sugimoto Y
Single amino acid substitutions in the transmembrane domains of breast cancer resistance protein (BCRP) alter cross resistance patterns in transfectants.
Int J Cancer. 2003 Dec 10;107(5):757-63., 2003-12-10 [PMID:14566825]
Abstract [show]
Breast cancer resistance protein (BCRP) is a member of ATP-binding cassette transporters that has an N-terminal ATP binding domain and a C-terminal transmembrane domain (TM). Expression of wild-type BCRP confers resistance to multiple chemotherapeutic agents such as mitoxantrone, SN-38 and topotecan, but not to doxorubicin. We made 32 BCRP mutants with an amino acid substitution in the TMs (7 E446-mutants in TM2, 15 R482-mutants in TM3, 4 N557-mutants in TM5 and 6 H630-mutants in TM6) and examined the effect of the substitutions on cellular drug resistance. PA317 cells transfected with any one of the 7 E446-mutant BCRP cDNAs did not show drug resistance. Cells transfected with any one of the 13 R482X2-BCRP cDNAs (X2 = N, C, M, S, T, V, A, G, E, W, D, Q and H, but not Y and K) showed higher resistance to mitoxantrone and doxorubicin than the wild-type BCRP-transfected cells. Cells transfected with N557D-BCRP cDNA showed similar resistance to mitoxantrone but lower resistance to SN-38 than the wild-type BCRP-transfected cells. Cells transfected with N557E-, H630E- or H630L-BCRP cDNA showed similar degrees of resistance to mitoxantrone and SN-38. Estrone and fumitremorgin C reversed the drug resistance of cells transfected with R482-, N557- or H630-mutant BCRP cDNA. Cells transfected with R482G- or R482S-BCRP cDNA showed less intracellular accumulation of [3H]mitoxantrone than the wild-type BCRP-transfected cells. These results suggest that E446 in TM2, R482 in TM3, N557 in TM5 and H630 in TM6 play important roles in drug recognition of BCRP.
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No. Sentence Comment
6 Cells transfected with N557E-, H630E- or H630L-BCRP cDNA showed similar degrees of resistance to mitoxantrone and SN-38.
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ABCG2 p.His630Glu 14566825:6:31
status: VERIFIED49 Among PA/ N557X3, PA/N557R expressed little BCRP. Among PA/H630X4 transfectants, moderate BCRP expression was observed in PA/ H630E.
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ABCG2 p.His630Glu 14566825:49:126
status: VERIFIED58 PA/H630E and PA/H630L also showed similar degrees of resistance to mitoxantrone and SN-38 (Fig.
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ABCG2 p.His630Glu 14566825:58:3
status: VERIFIED84 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.
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ABCG2 p.His630Glu 14566825:84:249
status: VERIFIED86 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).
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ABCG2 p.His630Glu 14566825:86:171
status: VERIFIED106 PA/N557E, PA/H630E and PA/H630L showed similar degrees of resistance to mitoxantrone and SN-38.
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ABCG2 p.His630Glu 14566825:106:13
status: VERIFIED140 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.
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ABCG2 p.His630Glu 14566825:140:630
status: VERIFIED143 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.
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ABCG2 p.His630Glu 14566825:143:752
status: VERIFIED[hide] Breast cancer resistance protein: molecular target... Cancer Sci. 2005 Aug;96(8):457-65. Sugimoto Y, Tsukahara S, Ishikawa E, Mitsuhashi J
Breast cancer resistance protein: molecular target for anticancer drug resistance and pharmacokinetics/pharmacodynamics.
Cancer Sci. 2005 Aug;96(8):457-65., [PMID:16108826]
Abstract [show]
Breast cancer resistance protein (BCRP) is a half-molecule ATP-binding cassette transporter that forms a functional homodimer and pumps out various anticancer agents, such as 7-ethyl-10-hydroxycamptothecin, topotecan, mitoxantrone and flavopiridol, from cells. Estrogens, such as estrone and 17beta-estradiol, have been found to restore drug sensitivity levels in BCRP-transduced cells by increasing the cellular accumulation of such agents. Furthermore, synthetic estrogens, tamoxifen derivatives and phytoestrogens/flavonoids have now been identified that can effectively circumvent BCRP-mediated drug resistance. Transcellular transport experiments have shown that BCRP transports sulfated estrogens and various sulfated steroidal compounds, but not free estrogens. The kinase inhibitor gefitinib inhibited the transporter function of BCRP and reversed BCRP-mediated drug resistance both in vitro and in vivo. BCRP-transduced human epidermoid carcinoma A431 (A431/BCRP) and BCRP-transduced human non-small cell lung cancer PC-9 (PC-9/BCRP) cells showed gefitinib resistance. Physiological concentrations of estrogens (10-100 pM) reduced BCRP protein expression without affecting its mRNA levels. Two functional polymorphisms of the BCRP gene have been identified. The C376T (Q126Stop) polymorphism has a dramatic phenotype as active BCRP protein cannot be expressed from a C376T allele. The C421A (Q141K) polymorphism is also significant as Q141K-BCRP-transfected cells show markedly low protein expression levels and low-level drug resistance. Hence, individuals with C376T or C421A polymorphisms may express low levels of BCRP or none at all, resulting in hypersensitivity of normal cells to BCRP-substrate anticancer agents. In summary, both modulators of BCRP and functional single nucleotide polymorphisms within the BCRP gene affect the transporter function of the protein and thus can modulate drug sensitivity and substrate pharmacokinetics and pharmacodynamics in affected cells and individuals.
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No. Sentence Comment
63 Cells transfected with N557E-BCRP, H630E-BCRP or H630L-BCRP cDNA showed similar degrees of resistance to mitoxantrone and SN-38.
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ABCG2 p.His630Glu 16108826:63:35
status: VERIFIED[hide] Multidrug resistance: retrospect and prospects in ... Curr Med Chem. 2006;13(16):1859-76. Perez-Tomas R
Multidrug resistance: retrospect and prospects in anti-cancer drug treatment.
Curr Med Chem. 2006;13(16):1859-76., [PMID:16842198]
Abstract [show]
Conventional cancer chemotherapy is seriously limited by the multidrug resistance (MDR) commonly exhibited by tumour cells. One mechanism by which a living cell can achieve multiple resistances is via the active efflux of a broad range of anticancer drugs through the cellular membrane by MDR proteins. Such drugs are exported in both ATP-dependent and -independent manners, and can occur despite considerable concentration gradients. To the ATP-dependent group belongs the ATP-binding cassette (ABC) transporter family, which includes P-gp, MRP, BCRP, etc. Another protein related to MDR, though not belonging to the ABC transporter family, is lung resistance-related protein (LRP). All of these proteins are involved in diverse physiological processes, and are responsible for the uptake and efflux of a multitude of substances from cancer cells. Many inhibitors of MDR transporters have been identified over the years. Firstly, MDR drugs were not specifically developed for inhibiting MDR; in fact, they had other pharmacological properties, as well as a relatively low affinity for MDR transporters. They included compounds of diverse structure and function, such as verapamil and cyclosporine, and caused side effects. Secondly, the new drugs were more inhibitor-specific, in terms of MDR transport, and were designed to reduce such side effects (e.g., R-verapamil, dexniguldipine, etc.). Unfortunately, they displayed poor response in clinical studies. Recently, new compounds obtained from drug development programs conducted by the pharmaceutical industry are characterized by a high affinity to MDR transporters and are efficient at nanomolar concentrations. Some of these compounds (e.g., MS-209) are currently under clinical trials for specific forms of advanced cancers. We aim to provide an overview of the properties associated with those mammalian MDR transporters known to mediate significant transport of relevant drugs in cancer treatments. We also summarize recent advances concerning resistance to cancer drug therapies with respect to the function and overexpression of ABC and LRP multidrug transporters.
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No. Sentence Comment
212 Cells transfected with N557E- or H630E or H630L-BCRP cDNA showed similar degrees of resistance to mitoxantrone and SN-38 than did wild-type BCRP-transfected cells.
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ABCG2 p.His630Glu 16842198:212:33
status: VERIFIED[hide] Towards understanding the mechanism of action of t... J Mol Graph Model. 2007 Mar;25(6):837-51. Epub 2006 Aug 30. Li YF, Polgar O, Okada M, Esser L, Bates SE, Xia D
Towards understanding the mechanism of action of the multidrug resistance-linked half-ABC transporter ABCG2: a molecular modeling study.
J Mol Graph Model. 2007 Mar;25(6):837-51. Epub 2006 Aug 30., [PMID:17027309]
Abstract [show]
The ATP-binding cassette protein ABCG2 is a member of a broad family of ABC transporters with potential clinical importance as a mediator of multidrug resistance. We carried out a homology and knowledge-based, and mutationally improved molecular modeling study to establish a much needed structural framework for the protein, which could serve as guidance for further genetic, biochemical, and structural analyses. Based on homology with known structures of both full-length and nucleotide-binding domains (NBD) of ABC transporters and structural knowledge of integral membrane proteins, an initial model of ABCG2 was established. Subsequent refinement to conform to the lipophilic index distributions in the transmembrane domain (TMD) and to the results of site-directed mutagenesis experiments led to an improved model. The complete ABCG2 model consists of two identical subunits facing each other in a closed conformation. The dimeric interface in the nucleotide-binding domain (NBD) involves a characteristic nucleotide sandwich and the interface in the TMD consists of the TM helices 1-3 of one subunit and the helices 5 and 6 of the other. The interface between the NBD and the TMD is bridged by the conserved structural motif between TM2 and TM3, the intracellular domain 1 (ICD1), and the terminal beta-strand (S6) of the central beta-sheet in the NBD. The apparent flexibility of the ICD1 may play a role in transmitting conformational changes from the NBD to the TMD or from the TMD to the NBD.
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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.
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ABCG2 p.His630Glu 17027309:182:402
status: VERIFIED[hide] Functions of the breast cancer resistance protein ... Adv Drug Deliv Rev. 2009 Jan 31;61(1):26-33. Epub 2008 Dec 3. Noguchi K, Katayama K, Mitsuhashi J, Sugimoto Y
Functions of the breast cancer resistance protein (BCRP/ABCG2) in chemotherapy.
Adv Drug Deliv Rev. 2009 Jan 31;61(1):26-33. Epub 2008 Dec 3., 2009-01-31 [PMID:19111841]
Abstract [show]
The breast cancer resistance protein, BCRP/ABCG2, is a half-molecule ATP-binding cassette transporter that facilitates the efflux of various anticancer agents from the cell, including 7-ethyl-10-hydroxycamptothecin, topotecan and mitoxantrone. The expression of BCRP can thus confer a multidrug resistance phenotype in cancer cells, and its transporter activity is involved in the in vivo efficacy of chemotherapeutic agents. Thus, the elucidation of the substrate preferences and structural relationships of BCRP is essential to understanding its in vivo functions during chemotherapeutic treatments. Single nucleotide polymorphisms (SNPs) have also been found to be key factors in determining the efficacy of chemotherapeutics, and those therapeutics that inhibit BCRP activity, such as the SNP that results in a C421A mutant, may result in unexpected side effects of the BCRP- anticancer drugs interaction even at normal dosages. In order to modulate the BCRP activity during chemotherapy, various compounds have been tested as inhibitors of this protein. Estrogenic compounds including estrone, several tamoxifen derivatives in addition to phytoestrogens and flavonoids have been shown to reverse BCRP-mediated drug resistance. Intriguingly, recently developed molecular targeted cancer drugs, such as the tyrosine kinase inhibitors imatinib mesylate, gefitinib and others, can also interact with BCRP. Since both functional SNPs and inhibitory agents of BCRP modulate the in vivo pharmacokinetics and pharmacodynamics of its substrate drugs, BCRP activity is an important consideration in the development of molecular targeted chemotherapeutics.
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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.
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ABCG2 p.His630Glu 19111841:839:41
status: VERIFIED