Taxol differentially modulates the dynamics of microtubules assembled from unfractionated and purified beta-tubulin isotypes
Taxol differentially modulates the dynamics of microtubules assembled from unfractionated and purified beta-tubulin isotypes
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DOI：
10.1021/bi962724m
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发表时间：
1997-03-25
期刊：
影响因子：
2.9
通讯作者：
Jordan, MA
中科院分区：
文献类型：
--
作者：
Derry, WB;Wilson, L;Jordan, MA
紫杉醇与微管中微管蛋白的亚化学计量结合有效地抑制微管动力学，这似乎是紫杉醇最敏感的抗增殖机制。为了确定微管的β-微管蛋白亚型组成是否可以调节对紫杉醇的敏感性，我们测量了微管中紫杉醇与微管蛋白结合的亚化学计量比对由纯化的α-β(II)-、α-β(III)-或α-β(IV)-微管蛋白组成的微管动力学的影响，并将结果与紫杉醇对由普通微管蛋白组成的微管的影响进行了比较。在由纯化的β-微管蛋白或未分离的微管蛋白组成的微管中，结合紫杉醇的亚化学计量比有效地抑制了缩短率和每个缩短事件的长度。结合紫杉醇的化学计量比与缩短速率的抑制相关表明，由纯化的α-β(II)-、α-β(III)-和α-β(IV)-微管蛋白组成的微管对结合紫杉醇的影响分别比由未分离的微管蛋白组装的微管低1.6、7.4和7.2倍。这些结果表明，紫杉醇对微管动力学的调节作用取决于β-微管蛋白的同型组成。这一结果与最近关于肿瘤细胞中紫杉醇耐药与β(III)和β(IV)-微管蛋白表达水平升高的研究相一致，并表明细胞中β-微管蛋白亚型表达的改变可能是肿瘤细胞对紫杉醇产生耐药的重要机制。
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 alpha beta(II)-, alpha beta(III)-, or alpha beta(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 alpha beta(II)-, alpha beta(III)-, and alpha beta(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(III)- 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.