ABCG2 p.Cys43Ala
| Predicted by SNAP2: | A: N (66%), D: D (66%), E: D (59%), F: N (53%), G: D (53%), H: N (72%), I: N (53%), K: D (53%), L: D (53%), M: D (53%), N: N (66%), P: D (66%), Q: N (57%), R: D (53%), S: N (78%), T: N (66%), V: N (61%), W: D (71%), Y: N (66%), |
| Predicted by PROVEAN: | A: N, D: N, E: N, F: N, G: N, H: N, I: N, K: N, L: N, M: N, N: N, P: N, Q: N, R: N, S: N, T: N, V: N, W: N, Y: N, |
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[hide] Effect of cysteine mutagenesis on the function and... J Pharmacol Exp Ther. 2008 Jul;326(1):33-40. Epub 2008 Apr 22. Liu Y, Yang Y, Qi J, Peng H, Zhang JT
Effect of cysteine mutagenesis on the function and disulfide bond formation of human ABCG2.
J Pharmacol Exp Ther. 2008 Jul;326(1):33-40. Epub 2008 Apr 22., [PMID:18430864]
Abstract [show]
ABCG2 is a member of the ATP-binding cassette (ABC) transporter superfamily. Its overexpression causes multidrug resistance in cancer chemotherapy. Based on its apparent half size in sequence when compared with other traditional ABC transporters, ABCG2 has been thought to exist and function as a homodimer linked by intermolecular disulfide bonds. However, recent evidence suggests that ABCG2 may exist as a higher form of oligomers due to noncovalent interactions. In this study, we attempted to create a cysless mutant ABCG2 as a tool for further characterization of this molecule. However, we found that the cysless mutant ABCG2 is well expressed but not functional. Mapping of the cysteine residues showed that three cysteine residues (Cys284, Cys374, and Cys438) are required concurrently for the function of ABCG2 and potentially for intramolecular disulfide bond formation. We also found that the cysteine residues (Cys592, Cys603, and Cys608) in the third extracellular loop are involved in forming intermolecular disulfide bonds and that mutation of these residues does not affect the expression or drug transport activity of human ABCG2. Thus, we conclude that Cys284, Cys374, and Cys438, which may be involved in intramolecular disulfide bond formation, are concurrently required for ABCG2 function, whereas Cys592, Cys603, and Cys608, potentially involved in intermolecular disulfide bond formation, are not required.
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111 Mutation of one or two of these residues (I2-CL, C284A, and C374A) did not signifi- TABLE 1 Primers used for construction of cysless mutants Mutations Primer Sequence RESa C43A TTTCATAACATTGCCTATCGAGTAAAACTGAAG BsrDI C55A GCTTTCTACCTGCACGAAAACCAGTTGAG BsgI C119A GCCAATTTCAAAGCGAATTCAGGTTACGTGG EcoRI C284A GAATCAGCTGGATATCACGCTGAGGCCTATAATAAC EcoRV C374A ACACCACCTCCTTCGCTCATCAACTCAGATG None C438A CTGACGACCAACCAAGCTTTCAGCAGTGTTTC HindIII C491A TATATTTACCGCTATAGTATACTTCATGTTAGG AccI C544A CTTCTCATGACGATCGCTTTTGTGTTTATGATG PvuI C592A GGACAAAACTTCGCCCCGGGACTCAATGCAA SmaI C603A/C608A AGGAAACAATCCTGCTAACTATGCAACAGCTACTGGCGAAGAATATTT -NspI C635A CACGTGGCCTTGGCTGCAATGATTGTTATTTTC BsrDI a Restriction (RES) enzyme digestion sites engineered in the primer for the convenience of detection.
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ABCG2 p.Cys43Ala 18430864:111:172
status: VERIFIED[hide] Association of multi-drug resistance gene polymorp... Cancer. 2011 Feb 15;117(4):744-51. doi: 10.1002/cncr.25510. Epub 2010 Oct 4. Tanaka M, Okazaki T, Suzuki H, Abbruzzese JL, Li D
Association of multi-drug resistance gene polymorphisms with pancreatic cancer outcome.
Cancer. 2011 Feb 15;117(4):744-51. doi: 10.1002/cncr.25510. Epub 2010 Oct 4., 2011-02-15 [PMID:20922799]
Abstract [show]
BACKGROUND: The purpose of this study was to identify single nucleotide polymorphisms (SNPs) of multidrug resistance genes that are associated with clinical outcome in patients with potentially resectable pancreatic adenocarcinoma who were treated with preoperative gemcitabine-based chemoradiotherapy at M. D. Anderson Cancer Center. METHODS: We selected 8 SNPs of 7 drug resistance genes, including MDR1 (ABCB1), MRP1-5 (ABCC1-5), and BCRP (ABCG2), reported to be important in mediating drug resistance. Genotype was determined by the Taqman method. The associations of genotype with tumor response to therapy and overall survival (OS) were evaluated using log-rank test, Cox regression, and logistic regression models. RESULTS: MRP5 A-2G AA genotype showed significant association with OS (log-rank P = .010). The hazard ratio (95% confidence interval) was 1.65 (1.11-2.45) after adjusting for clinical predictors. The MRP2 G40A GG genotype had a weak association with reduced OS (log-rank P = .097). A combined effect of the two genotypes on OS was observed. Patients with none of the adverse genotypes had a median survival time (MST) of 34.0 months, and those with 1-2 deleterious alleles had a significantly lower MST of 20.7 months (log-rank P = .006). MRP2 G40A GG genotype was also significantly associated with poor histological response to chemoradiotherapy (P = .028). CONCLUSIONS: These observations suggest a potential role of polymorphic variants of drug resistance genes in predicting therapeutic efficacy and survival of patients with potentially resectable pancreatic cancer.
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88 Overall Survival by Genotype Genotype No. of Patients No. of Deaths MST6SE (Months) Log-Rank P HRa (95% CI) P MDR1 T-55C CC 45 32 23.8Æ5.3 CT 64 46 21.5Æ3.3 TT 43 31 21.7Æ3.4 .982 CC vs TT/CT .869 1.24 (0.81-1.90) .317 MRP1 G36A GG 81 64 21.5Æ2.4 AG 60 38 23.9Æ9.3 AA 13 9 21.4Æ6.1 .247 AA/AG vs GG .136 1.03 (0.69-1.53) .890 MRP2 G40A GG 86 67 21.2Æ2.6 AG 55 34 31.0Æ7.1 AA 10 7 17.5Æ4.8 .172 AG/AA vs GG .097 1.55 (1.02-2.36) .040 MRP2 C-16T CC 63 44 23.9Æ4.2 CT 69 49 20.7Æ4.0 TT 19 15 22.5Æ2.2 .962 CC vs TT/CT .785 1.13 (0.75-1.69) .557 MRP3 C-13T CC 89 67 21.4Æ2.3 CT 47 32 28.7Æ7.0 TT 13 8 23.9Æ10.9 .307 CT/TT vs CC .129 1.10 (0.72-1.67) .664 MRP4 A40G GG 54 34 26.4Æ8.1 AG 76 58 21.7Æ2.4 AA 22 17 14.6Æ2.6 .172 GG/AG vs AA .158 1.29 (0.75-2.23) .357 MRP5 A-2G AA 68 54 18.4Æ3.0 AG 62 38 31.0Æ4.2 GG 22 17 20.7Æ7.0 .017 AG/GG vs AA .010 1.65 (1.11-2.45) .013 BCRP C43A CC 116 83 23.9Æ3.3 AC 27 19 21.2Æ0.8 AA 4 3 20.4Æ10.0 .960 AA/AC vs CC .960 1.05 (0.65-1.72) .834 No. of deleterious allelesb .006 0 39 21 34.0Æ12.0 1-2 112 87 20.7Æ1.5 2.18 (1.32-3.60) .002 MST, median survival time; SE, standard error; HR, Hazard ratio a HR was adjusted for history of diabetes, tumor size, serum level of CA19-9, tumor response, and tumor resection.
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ABCG2 p.Cys43Ala 20922799:88:977
status: NEW116 Although MDR1 T-55C and BCRP C43A were reported to be functional SNPs that change their protein functions,25,29 none of these SNPs-nor the MRP1, MRP3, or MRP4 gene SNPs examined in this study-had any association with overall survival or tumor response to therapy.
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ABCG2 p.Cys43Ala 20922799:116:29
status: NEW