Taxol differentially modulates the dynamics of microtubules assembled from unfractionated and purified beta-tubulin isotypes.
Substoichiometric binding of taxol to tubulin in microtubules potently suppresses microtubule dynamics, which appears to be the most sensitive antiproliferative mechanism of taxol. To determine whether the beta-tubulin isotype composition of a microtubule can modulate sensitivity to taxol, we measured the effects of substoichiometric ratios of taxol bound to tubulin in microtubules on the dynamics of microtubules composed of purified alphabeta(II)-, alphabeta(III)-, or alphabeta(IV)-tubulin isotypes and compared the results with the effects of taxol on microtubules assembled from unfractionated tubulin. Substoichiometric ratios of bound taxol in microtubules assembled from purified beta-tubulin isotypes or unfractionated tubulin potently suppressed the shortening rates and the lengths shortened per shortening event. Correlation of the suppression of the shortening rate with the stoichiometry of bound taxol revealed that microtubules composed of purified alphabeta(II)-, alphabeta(III)-, and alphabeta(IV)-tubulin were, respectively, 1.6-, 7.4-, and 7.2-fold less sensitive to the effects of bound taxol than microtubules assembled from unfractionated tubulin. These results indicate that taxol differentially modulates microtubule dynamics depending upon the beta-tubulin isotype composition. The results are consistent with recent studies correlating taxol resistance in tumor cells with increased levels of beta(III0- and beta(IV)-tubulin expression and suggest that altered cellular expression of beta-tubulin isotypes can be an important mechanism by which tumor cells develop resistance to taxol.
Derry
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WB
Department of Molecular, Cellular, and Developmental Biology, University of California, Santa Barbara 93106, USA.
Wilson
L
L
Khan
I A
IA
Luduena
R F
RF
Jordan
M A
MA
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000494:pharmacology*; D001923:Brain Chemistry; D002417:Cattle; D007700:Kinetics; D018715:Microscopy, Video; D008870:Microtubules / Q000187:drug effects* / Q000378:metabolism; D017239:Paclitaxel / Q000008:administration & dosage / Q000494:pharmacology*; D011108:Polymers / Q000378:metabolism; D013329:Structure-Activity Relationship; D013997:Time Factors; D014404:Tubulin / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism*
D000972:Antineoplastic Agents, Phytogenic; D011108:Polymers; D014404:Tubulin; D017239:Paclitaxel