Department of Integrative Biology and Pharmacology, University of Texas Medical School, Houston, Texas 77030, USA.
J Biol Chem. 2010 Oct 15;285(42):32242-50. doi: 10.1074/jbc.M110.160820. Epub 2010 Aug 9.
Drugs that target microtubules are thought to inhibit cell division and cell migration by suppressing dynamic instability, a "search and capture" behavior that allows microtubules to probe their environment. Here, we report that subtoxic drug concentrations are sufficient to inhibit plus-end microtubule dynamic instability and cell migration without affecting cell division or microtubule assembly. The higher drug concentrations needed to inhibit cell division act through a novel mechanism that generates microtubule fragments by stimulating microtubule minus-end detachment from their organizing centers. The frequency of microtubule detachment in untreated cells increases at prophase suggesting that it is a regulated cellular process important for spindle assembly and function. We conclude that drugs produce differential dose-dependent effects at microtubule plus and minus-ends to inhibit different microtubule-mediated functions.
靶向微管的药物被认为通过抑制动态不稳定性来抑制细胞分裂和细胞迁移，动态不稳定性是一种“搜索和捕获”行为，允许微管探测其环境。在这里，我们报告亚毒性药物浓度足以抑制正极微管动态不稳定性和细胞迁移，而不影响细胞分裂或微管组装。抑制细胞分裂所需的更高药物浓度通过一种新的机制起作用，该机制通过刺激微管从其组织中心的负端脱离来产生微管片段。在未处理的细胞中，前期微管脱离的频率增加，表明这是一个受调控的细胞过程，对纺锤体组装和功能很重要。我们得出结论，药物在微管的正极和负极产生不同的剂量依赖性效应，以抑制不同的微管介导的功能。
