Kinesin-regulated microtubule dynamics

描述(申请人提供)：成功的细胞分裂需要动态微管聚合物。由于微管在有丝分裂中的中心作用，抑制微管动力学的药物有效地扰乱了细胞分裂，通常被用作抗癌药物。体内的辅助蛋白严密地调节微管动力学。促进微管更新的蛋白质异常高表达与对微管毒素治疗耐药的侵袭性肿瘤有关。详细的研究重点是了解这些辅助蛋白的功能，这可能会为新的化疗策略铺平道路。这项拟议的研究旨在精确定义三种相关的激动素样马达蛋白如何影响微管动力学，以促进人类细胞中适当的有丝分裂染色体分离。敏感的分析将被用来直接测量这些动蛋白的机械力化学性质和细胞功能。这项工作的目标是充分了解Kinesin-8蛋白如何在其他微管动力学调节器的背景下发挥作用，以确保细胞成功分裂。确定微管细胞骨架调节因子之间的功能关系将为癌症生物学的研究提供新的方向。

DESCRIPTION (provided by applicant): Dynamic microtubule polymers are required for successful cell division. Due to the central role of microtubules in mitosis, pharmacological agents that suppress microtubule dynamics effectively disrupt cell division and are commonly used as anti-cancer drugs. Accessory proteins in vivo tightly regulate microtubule dynamics. Abnormally high expression of proteins that promote microtubule turnover is correlated with aggressive tumors that are resistant to treatment with microtubule poisons. Detailed studies focused on understanding how these accessory proteins function will likely pave the way to new chemotherapeutic strategies. The proposed study aims to precisely define how three related kinesin-like motor proteins affect microtubule dynamics to promote proper mitotic chromosome segregation in human cells. Sensitive assays will be employed to directly measure the mechanochemical properties and cellular functions of these kinesins. The goal of this work is to fully understand how kinesin-8 proteins function in the context of other modulators of microtubule dynamics to ensure successful cell division. Defining the functional relationships between regulators of the microtubule cytoskeleton will foster new directions for the study of cancer biology.