Effects of anti-microtubule agents on microtubule organization in cells lacking the kinesin-13 MCAK
Effects of anti-microtubule agents on microtubule organization in cells lacking the kinesin-13 MCAK
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DOI：
10.4161/cc.7.14.6239
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发表时间：
2008-07-15
期刊：
影响因子：
4.3
通讯作者：
Walczak, Claire E.
中科院分区：
文献类型：
--
作者：
Hedrick, David G.;Stout, Jane R.;Walczak, Claire E.
动态微管是有丝分裂纺锤体组装和染色体分离所必需的。分子马达蛋白驱动蛋白超家族的成员对于纺锤体功能是重要的。特别令人感兴趣的是驱动蛋白-13家族成员MCAK，其作用是在纺锤体组装过程中调节微管动力学，并确保染色体与纺锤体微管的适当附着。MCAK调节微管动力学的独特能力使其成为开发改变纺锤体功能的新药的潜在靶点。在这里，我们通过RNAi在正常和恶性细胞系中敲低MCAK，发现两种测试的恶性细胞系对MCAK敲低非常敏感，而测试的正常细胞不太敏感。此外，我们研究了MCAK敲除和紫杉醇或长春碱药物治疗相结合的效果，以确定纺锤体组装缺陷。我们发现，MCAK敲低增加了由抗微管药物引起的HeLa细胞中微管细胞骨架的形态缺陷。我们的研究支持这样的想法，即MCAK将是一个很好的新的化疗药物开发的目标，并可能是特别有用的组合疗法与目前可用的抗微管剂。
Dynamic microtubules are necessary for proper mitotic spindle assembly and chromosome segregation during mitosis. Members of the kinesin superfamily of molecular motor proteins are important to spindle function. Of particular interest is the Kinesin-13 family member MCAK, which acts to regulate microtubule dynamics during spindle assembly and to ensure proper attachments of chromosomes to spindle microtubules. The unique ability of MCAK to regulate microtubule dynamics makes it a potential target for development of new drugs that alter spindle function. Here, we knocked down MCAK via RNAi in normal and malignant cell lines and found that the two tested malignant cell lines were acutely sensitive to MCAK knockdown, while the tested normal cells were less sensitive. In addition, we looked at the effect of combining MCAK knockdown and drug treatment with paclitaxel or vinblastine to identify spindle assembly defects. We found that MCAK knockdown increased the morphological defects of the microtubule cytoskeleton in HeLa cells caused by anti-microtubule drugs. Our studies support the idea that MCAK would be a good target for new chemotherapeutic development and may be particularly useful in combination therapies with currently available anti-microtubule agents.