The role of β-tubulin isotypes in resistance to antimitotic drugs

Burkhart, Catherine; Kavallaris, Maria; Horwitz, Susan Band

doi:10.1016/s0304-419x(00)00022-6

Cited by 139 publications

(159 citation statements)

References 50 publications

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“…The b-tubulin isotype composition of microtubules in vitro can alter their dynamic properties (Panda et al, 1994;Derry et al, 1997), suggesting that the differences we observed in isotype composition between wt-p53 and mut-p53 cells may contribute to the observed differences in dynamics. These alterations may also be involved in drug resistance to microtubule-targeted drugs (Burkhart et al, 2001). The greatly increased expression of Class IV b-tubulin we observed would be predicted to result in increased resistance to paclitaxel (Derry et al, 1997), just as we observed for the mut-p53 cells.…”

Section: Discussionsupporting

confidence: 66%

Drug resistance associated with loss of p53 involves extensive alterations in microtubule composition and dynamics

et al. 2003

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In the present study, we compared the dynamics and composition of microtubules in cell lines derived from the human breast adenocarcinoma MCF-7 containing either the wild-type p53 (wt-p53; MN1) or a dominant-negative variant of p53 gene (mut-p53; MDD2). Mut-p53 cells were significantly resistant to the cytotoxicity of the microtubule-targeted drugs (vinca alkaloids and taxanes), as compared with wt-p53 cells. Studies by high-resolution time-lapse fluorescence microscopy in living cells indicated that the dynamics of microtubules of mut-p53 cells were altered in complex ways and were significantly increased as compared with microtubules in wt-p53 cells. The percentage of time microtubules spent in growing and shortening phases increased significantly, their catastrophe frequency increased, and their overall dynamicity increased by 33%. In contrast, their shortening rate and the mean length shortened decreased. Cells containing mut-p53 displayed increased polymerisation of tubulin, increased protein levels of the class IV b-tubulin isotype, STOP and survivin, and reduced protein levels of class II b-tubulin isotype, MAP4 and FHIT. We conclude that p53 protein may contribute to the regulation of microtubule composition and function, and that alterations in p53 function may generate complex microtubule-associated mechanisms of resistance to tubulin-binding agents.

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Section: Discussionsupporting

confidence: 66%

Drug resistance associated with loss of p53 involves extensive alterations in microtubule composition and dynamics

et al. 2003

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“…Increased b-tubulin enhances the dynamic instability of the microtubules that is needed for cell division to occur. Mutations in human class I (M40) b-tubulin have been reported in several resistant cell lines, to both microtubule-stabilizing and -destabilizing agents [65][66][67]. Altered expression of tubulin isotypes and altered expression of microtubule-associated proteins have also been associated with drug resistance [65][66][67][68][69].…”

Section: Proteins Involved In Cell Regulationmentioning

confidence: 99%

Searching for potential biomarkers of cisplatin resistance in human ovarian cancer using a label‐free LC/MS‐based protein quantification method

Fitzpatrick

You²,

Bemis³

et al. 2007

Proteomics Clinical Apps

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Platinum-based chemotherapy, such as cisplatin, is the primary treatment for ovarian cancer. However, drug resistance has become a major impediment to the successful treatment of ovarian cancer. To date, the molecular mechanisms of resistance to platinum-based chemotherapy remain unclear. In this study, we applied an LC/MS-based protein quantification method to examine the global protein expression of two pairs of ovarian cancer cell lines, A2780/A2780-CP (cisplatin-sensitive/cisplatin-resistant) and 2008/2008-C13*5.25 (cisplatin-sensitive/cisplatinresistant). We identified and quantified over 2000 proteins from these cell lines and 760 proteins showed significant expression changes with a false discovery rate of less than 5% between paired groups. Based on the results we obtained, we suggest several potential pathways that may be involved in cisplatin resistance in human ovarian cancer. This study provides not only a new proteomic platform for large-scale quantitative protein analysis, but also important information for discovery of potential biomarkers of cisplatin resistance in ovarian cancer. Furthermore, these results may be clinically relevant for diagnostics, prognostics, and therapeutic improvement for ovarian cancer treatment.

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“…These include P-glycoprotein -mediated multidrug resistance (MDR; ref. 18), changes in microtubule assembly that counteract the effects of the drugs (19), alterations in drug binding affinity (20,21), and changes in the expression levels of particular h-tubulin isotypes (22).…”

Section: Introductionmentioning

confidence: 99%

Amino acid substitutions at proline 220 of β-tubulin confer resistance to paclitaxel and colcemid

Yin

Cabral

Veeraraghavan³

2007

Molecular Cancer Therapeutics

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Chinese hamster ovary cells selected for resistance to paclitaxel have a high incidence of mutations affecting L215, L217, and L228 in the H6/H7 loop region of B1-tubulin. To determine whether other mutations in this loop are also capable of conferring resistance to drugs that affect microtubule assembly, saturation mutagenesis of the highly conserved P220 codon in B1-tubulin cDNA was carried out. Transfection of a mixed pool of plasmids encoding all possible amino acid substitutions at P220 followed by selection in paclitaxel produced cell lines containing P220L and P220V substitutions. Similar selections in colcemid, on the other hand, yielded cell lines with P220C, P220S, and P220T substitutions. Site-directed mutagenesis and retransfection confirmed that these mutations were responsible for drug resistance. Expression of tubulin containing the P220L and P220V mutations reduced microtubule assembly, conferred resistance to paclitaxel and epothilone A, but increased sensitivity to colcemid and vinblastine. In contrast, tubulin with the P220C, P220S, and P220T mutations increased microtubule assembly, conferred resistance to colcemid and vinblastine, but increased sensitivity to paclitaxel and epothilone A. The results are consistent with molecular modeling studies and support a drug resistance mechanism based on changes in microtubule assembly that counteract the effects of drug treatment. These studies show for the first time that different substitutions at the same amino acid residue in B1-tubulin can confer cellular resistance to either microtubule-stabilizing or microtubule-destabilizing drugs. [Mol Cancer Ther 2007; 6(10):2798 -806]

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The role of β-tubulin isotypes in resistance to antimitotic drugs

Cited by 139 publications

References 50 publications

Drug resistance associated with loss of p53 involves extensive alterations in microtubule composition and dynamics

Drug resistance associated with loss of p53 involves extensive alterations in microtubule composition and dynamics

Searching for potential biomarkers of cisplatin resistance in human ovarian cancer using a label‐free LC/MS‐based protein quantification method

Amino acid substitutions at proline 220 of β-tubulin confer resistance to paclitaxel and colcemid

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