ABCB1 p.Asp26Glu
| Predicted by SNAP2: | A: N (78%), C: N (57%), E: N (93%), F: N (66%), G: N (78%), H: N (78%), I: N (72%), K: N (87%), L: N (72%), M: N (78%), N: N (82%), P: N (78%), Q: N (87%), R: N (82%), S: N (93%), T: N (87%), V: N (78%), W: N (53%), Y: N (57%), |
| Predicted by PROVEAN: | A: N, C: D, E: N, F: D, G: N, H: N, I: D, K: N, L: D, M: N, N: N, P: N, Q: N, R: N, S: N, T: N, V: N, W: D, Y: N, |
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[hide] Paclitaxel-resistant cells have a mutation in the ... Mol Cancer Ther. 2006 Feb;5(2):270-8. Hari M, Loganzo F, Annable T, Tan X, Musto S, Morilla DB, Nettles JH, Snyder JP, Greenberger LM
Paclitaxel-resistant cells have a mutation in the paclitaxel-binding region of beta-tubulin (Asp26Glu) and less stable microtubules.
Mol Cancer Ther. 2006 Feb;5(2):270-8., [PMID:16505100]
Abstract [show]
Resistance to paclitaxel-based therapy is frequently encountered in the clinic. The mechanisms of intrinsic or acquired paclitaxel resistance are not well understood. We sought to characterize the resistance mechanisms that develop upon chronic exposure of a cancer cell line to paclitaxel in the presence of the P-glycoprotein reversal agent, CL-347099. The epidermoid tumor line KB-3-1 was exposed to increasing concentrations of paclitaxel and 5 micromol/L CL-347099 for up to 1 year. Cells grown in 15 nmol/L paclitaxel plus CL-347099 (KB-15-PTX/099) developed 18-fold resistance to paclitaxel and were dependent upon paclitaxel for maximal growth. They grew well and retained resistance to paclitaxel when grown in athymic mice. Cross-resistance (3- to 5-fold) was observed in tissue culture to docetaxel, the novel taxane MAC-321, and epothilone B. Collateral sensitivity (approximately 3-fold) was observed to the depolymerizing agents vinblastine, dolastatin-10, and HTI-286. KB-15-PTX/099-resistant cells did not overexpress P-glycoprotein nor did they have an alteration of [14C]paclitaxel accumulation compared with parental cells. However, a novel point mutation (T to A) resulting in Asp26 to glutamate substitution in class I (M40) beta-tubulin was found. Based on an electron crystallography structure of Zn-stabilized tubulin sheets, the phenyl ring of C-3' NHCO-C6H5 of paclitaxel makes contact with Asp26 of beta-tubulin, suggesting a ligand-induced mutation. Optimized model complexes of paclitaxel, docetaxel, and MAC-321 in beta-tubulin show a novel hydrogen bonding pattern for the glutamate mutant and rationalize the observed resistance profiles. However, a mutation in the paclitaxel binding pocket does not explain the phenotype completely. KB-15-PTX/099 cells have impaired microtubule stability as determined by a reduced percentage of tubulin in microtubules and reflected by less acetylated tubulin. These results suggest that a mutation in tubulin might affect microtubule stability as well as drug binding and contribute to the observed resistance profile.
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No. Sentence Comment
123 Sequencing revealed that class I h-tubulin of KB-15-PTX/099 cells encodes for a point mutation at residue Asp26 Glu (GAT to GAA) compared with the wild-type sequence (see Supplementary Fig. S1).3 This mutation is in the NH2 terminus of h-tubulin and is part of the binding pocket of paclitaxel (ref. 34; see Discussion).
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ABCB1 p.Asp26Glu 16505100:123:106
status: NEW125 Amino acid sequencing confirmed that the Asp26 Glu mutation was expressed in the h-tubulin protein isolated from KB-15-PTX/099 cells.
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ABCB1 p.Asp26Glu 16505100:125:41
status: NEW154 These cells (a) are resistant to paclitaxel and cross-resistant to other tubulin polymerizing agents, yet are collaterally sensitive to microtubule depolymerizing agents; (b) are partially growth-dependent on paclitaxel or other tubulin polymerizing drugs; (c) contain a mutation in h-tubulin protein that substitutes glutamate for aspartate at position 26; and (d) have less stable microtubules compared with parental cells.
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ABCB1 p.Asp26Glu 16505100:154:318
status: NEW174 The mutation in h-tubulin Asp26 Glu is unique because it seems to be in the contact site for paclitaxel but is also associated with a change in microtubule stability.
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ABCB1 p.Asp26Glu 16505100:174:26
status: NEW175 In support of the important role of Asp26 in paclitaxel binding and tubulin function, a h-tubulin mutation converting Asp26 to glutamate was also recently reported in paclitaxel-resistant Chinese hamster ovary cells (37).
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ABCB1 p.Asp26Glu 16505100:175:118
status: NEW176 The exogenous expression of Asp26 Glu h-tubulin in a wild-type background conferred resistance to paclitaxel and sensitivity to colcemid and vinblastine.
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ABCB1 p.Asp26Glu 16505100:176:28
status: NEW183 Reappearance of wild-type tubulin could also be explained by the selection of revertants because cells bearing the Asp26 Glu mutation depend on paclitaxel for growth and may not survive extended passage without the drug.
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ABCB1 p.Asp26Glu 16505100:183:115
status: NEW184 Asp26 Mutation The mutation of Asp26 to glutamate in h-tubulin detected in KB-15-PTX/099 cells is likely to reside in a contact site for paclitaxel based on biochemical and structural studies.
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ABCB1 p.Asp26Glu 16505100:184:31
status: NEW214 To examine the effect of the Asp26 Glu mutation, we adopted a strategy that initially examined the different rotamers of the glutamate residue in the mutant in the energy-optimized models.
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ABCB1 p.Asp26Glu 16505100:214:29
status: NEW224 Analysis of nonbonded interactions in the separate h-tubulin models of paclitaxel, docetaxel, and MAC-321 implies that relative binding affinities to the Asp26 Glu mutant in the KB-15-PTX/099 cell line are paclitaxel < docetaxel V MAC-321.
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ABCB1 p.Asp26Glu 16505100:224:154
status: NEW227 In general, tighter binding drugs should increase rather than decrease cell kill, assuming that the only change in assay and cell conditions is the Asp26 Glu mutation.
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ABCB1 p.Asp26Glu 16505100:227:148
status: NEW245 The Asp26 Glu point mutation is at the drug binding site and is associated with a change in the stability of microtubules.
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ABCB1 p.Asp26Glu 16505100:245:4
status: NEW[hide] Carboplatin and taxol resistance develops more rap... Exp Cell Res. 2015 Aug 1;336(1):1-14. doi: 10.1016/j.yexcr.2014.12.001. Epub 2014 Dec 12. Busschots S, O'Toole S, O'Leary JJ, Stordal B
Carboplatin and taxol resistance develops more rapidly in functional BRCA1 compared to dysfunctional BRCA1 ovarian cancer cells.
Exp Cell Res. 2015 Aug 1;336(1):1-14. doi: 10.1016/j.yexcr.2014.12.001. Epub 2014 Dec 12., [PMID:25499884]
Abstract [show]
A major risk factor for ovarian cancer is germline mutations of BRCA1/2. It has been found that (80%) of cellular models with acquired platinum or taxane resistance display an inverse resistance relationship, that is collateral sensitivity to the other agent. We used a clinically relevant comparative selection strategy to develop novel chemoresistant cell lines which aim to investigate the mechanisms of resistance that arise from different exposures of carboplatin and taxol on cells having BRCA1 function (UPN251) or dysfunction (OVCAR8). Resistance to carboplatin and taxol developed quicker and more stably in UPN251 (BRCA1-wildtype) compared to OVCAR8 (BRCA1-methylated). Alternating carboplatin and taxol treatment delayed but did not prevent resistance development when compared to single-agent administration. Interestingly, the sequence of drug exposure influenced the resistance mechanism produced. UPN251-6CALT (carboplatin first) and UPN251-6TALT (taxol first) have different profiles of cross resistance. UPN251-6CALT displays significant resistance to CuSO4 (2.3-fold, p=0.004) while UPN251-6TALT shows significant sensitivity to oxaliplatin (0.6-fold, p=0.01). P-glycoprotein is the main mechanism of taxol resistance found in the UPN251 taxane-resistant sublines. UPN251 cells increase cellular glutathione levels (3.0-fold, p=0.02) in response to carboplatin treatment. However, increased glutathione is not maintained in the carboplatin-resistant sublines. UPN251-7C and UPN251-6CALT are low-level resistant to CuSO4 suggesting alterations in copper metabolism. However, none of the UPN251 sublines have alterations in the protein expression of ATP7A or CTR1. The protein expression of BRCA1 and MRP2 is unchanged in the UPN251 sublines. The UPN251 sublines remain sensitive to parp inhibitors veliparib and CEP8983 suggesting that these agents are candidates for the treatment of platinum/taxane resistant ovarian cancer patients.
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No. Sentence Comment
411 [63] M. Hari, F. Loganzo, T. Annable, X. Tan, S. Musto, D.B. Morilla, J.H. Nettles, J.P. Snyder, L.M. Greenberger, Paclitaxel-resistant cells have a mutation in the paclitaxel-binding region of Beta-tubulin (Asp26Glu) and less stable microtubules, Mol. Cancer Ther. 5 (2) (2006) 270-278.
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ABCB1 p.Asp26Glu 25499884:411:208
status: NEW