ABCMdb

PMID: 16505100

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., [PubMed]

Sentences

No. Mutations Sentence Comment

123 ABCB1 p.Asp26Glu 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). Login to comment 125 ABCB1 p.Asp26Glu Amino acid sequencing confirmed that the Asp26 Glu mutation was expressed in the h-tubulin protein isolated from KB-15-PTX/099 cells. Login to comment 154 ABCB1 p.Asp26Glu 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. Login to comment 174 ABCB1 p.Asp26Glu 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. Login to comment 175 ABCB1 p.Asp26Glu 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). Login to comment 176 ABCB1 p.Asp26Glu The exogenous expression of Asp26 Glu h-tubulin in a wild-type background conferred resistance to paclitaxel and sensitivity to colcemid and vinblastine. Login to comment 183 ABCB1 p.Asp26Glu 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. Login to comment 184 ABCB1 p.Asp26Glu 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. Login to comment 194 ABCB4 p.Ala364Thr This has been observed in 1A9 cells made resistant to paclitaxel that harbor the mutation Phe270 Val or Ala364 Thr, where mutant tubulin mRNA is preferentially expressed. Login to comment 214 ABCB1 p.Asp26Glu 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. Login to comment 224 ABCB1 p.Asp26Glu 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. Login to comment 227 ABCB1 p.Asp26Glu 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. Login to comment 245 ABCB1 p.Asp26Glu The Asp26 Glu point mutation is at the drug binding site and is associated with a change in the stability of microtubules. Login to comment