CELL CYCLE REGULATION OF GOLGI MEMBRANE DYNAMICS

 描述（由申请方提供）：细胞增殖主要依赖于间期细胞器的复制和有丝分裂期间两个子细胞之间的分离。染色体和细胞内细胞器的精确划分对于维持细胞功能的世代至关重要。有丝分裂缺陷可导致基因组不稳定和重要细胞器的丢失，这通常与癌症的发展有关。虽然已经取得了很大的进展，了解染色体的分离，管理重要的细胞器，特别是高尔基体的分区的机制，仍然在很大程度上是未知的。哺乳动物的高尔基体是分泌和有丝分裂后的细胞生存所必需的，取决于功能的高尔基体到后代的分配。我们的目的是确定潜在的机制，确保忠实的分区的单个哺乳动物高尔基体在有丝分裂。在有丝分裂开始时，高度组织化的高尔基体结构囊泡化，并在两个子细胞中平均分配后重新形成。我们以前表明，纺锤体积极分区哺乳动物高尔基体。这一过程是由高尔基体膜蛋白GM 130启动的，它局部激活纺锤体组装因子TPX 2以启动微管聚合。形成的微管被GM 130进一步捕获和捆绑，从而将高尔基体膜连接到纺锤体，以确保高尔基体分离到子细胞中。在这个建议中，我们计划确定这个过程的生物化学和机制基础。我们的目的是确定结合伙伴和功能开关的GM 130在有丝分裂的分子基础;解剖GM 130的微管成核，捆绑和Ran依赖性在高尔基体衍生的纺锤体组装的功能;并阐明高尔基体囊泡化在有丝分裂进程中的作用。这些研究将为有丝分裂和高尔基体分裂过程的调控提供新的分子机制见解。

 DESCRIPTION (provided by applicant): Cell proliferation critically depends on the duplication organelles in interphase and the segregation between the two daughter cells during mitosis. Accurate partitioning of chromosomes and intracellular organelles is crucial to sustain cellular functions over generations. Defects in mitosis can lead to genomic instability and loss of vital organelles, which is commonly associated with the development of cancer. While much progress has been made towards understanding the segregation of chromosomes, the mechanisms that govern the partitioning of vital organelles, in particular of the Golgi, remain largely unknown. The mammalian Golgi is essential for secretion and post-mitotic cell survival depends on the partitioning of a functional Golgi into progeny. Our aim is to define the underlying mechanisms that ensure the faithful partitioning of the single mammalian Golgi during mitosis. At the onset of mitosis, the highly organized Golgi structure vesiculates and reforms after equal partitioning in the two daughter cells. We previously showed that the spindle actively partitions the mammalian Golgi. This process is initiated by the Golgi membrane protein GM130, which locally activates the spindle assembly factor TPX2 to initiate microtubule polymerization. Forming microtubules are further captured and bundled by GM130, thereby linking Golgi membranes to the spindle to ensure the Golgi segregation into the daughter cells. In this proposal we plan to determine the biochemical and mechanistic basis for this process. Our aims are to determine the molecular basis for binding partner and functional switching of GM130 in mitosis; to dissect GM130 functions in microtubule nucleation, bundling and Ran dependency in Golgi-derived spindle assembly; and to elucidate the role of Golgi vesiculation in mitotic progression. Together these studies will provide new molecular mechanistic insights into the regulation of mitosis and the division process of the Golgi apparatus.