POLO KINASES IN CELL PROLIFERATION AND DEVELOPMENT

描述(来自应用程序)：POLO蛋白激酶家族现在是 已知在扩散中起着关键作用。在高等真核生物中，苍蝇， 酵母Polo激酶同系物对细胞周期进程是必不可少的 通过M期。在哺乳动物中，不同的Polo激酶--例如SNK--也是 在细胞周期早期表达。哺乳动物的酶，特别是PLK和PLK SNK是本申请中提出的研究重点。除了……之外 催化激酶结构域，Polo激酶在 C-末端，表示马球盒子。马球盒子的突变破坏了细胞 用野生型PLK观察到定位，损害了PLK的有丝分裂功能。 将确定Polo盒相互作用的蛋白质，并将其潜在地 影响中心体的生物发生和功能以及Septin的定位 和组织，将被确定。 将通过筛选进行SNK和PLK底物的一般搜索 表达文库，并通过改造这些酶来获得 利用其他酶不能有效利用的ATP类似物。在……里面 为了更准确地表征SNK的功能，胚胎干细胞将 通过有针对性的基因破坏而产生。这些细胞将被用来 获得具有生殖系传播的小鼠，以确定其潜在作用 SNK在胚胎发育中的作用。 这些研究与癌症有直接关系，因为有序的分离 两个子细胞的染色体需要不受损害的PLK功能。直到 最近，非整倍体在癌细胞中表现出 染色体数目异常，被认为是一种结果，而不是 原因，是恶性的。然而，最近的研究表明，非整倍体可能会导致 癌症。中心体在维持完整性方面起着关键作用。 人类基因组的。异常中心体结构与非整倍体紧密相关 与晚期肿瘤相关。这里提出的研究涉及分子 由PLK控制的涉及中心体复制和启动的事件 解理沟的形成和SNK对这些和其他的影响的潜力 特定单元格类型中的事件。

DESCRIPTION (from the application): The polo family of protein kinases is now known to have a critical role in proliferation. In higher eukaryotes, flies, and yeast polo kinase homologues are essential for cell cycle progression through M phase. In mammals, distinct polo kinases -for example, Snk-are also expressed early in the cell cycle. The mammalian enzymes, particularly Plk and Snk are the focus of the studies proposed in this application. IN addition to the catalytic kinase domain, polo kinases have a conserved sequence in the C-terminus, denoted the polo box. Polo box mutations disrupt the cellular localization observed with wild-type Plk and compromise Plk mitotic functions. Polo box interacting proteins will be identified and their potential to influence centrosome biogenesis and function, as well as septin localization and organization, will be determined. A general search for Snk and Plk substrates will be conducted by screening expression libraries and by engineering these enzymes to attain the capacity to utilize ATP analogues that will not be used efficiently by other kinases. In order to more precisely characterize Snk functions, embryonic stem cells will be generated with a targeted gene disruption. These cells will be used to obtain mice with germline transmission in order to determine the potential role of Snk in embryonic development. These studies have direct relevance to cancer, as the ordered segregation of chromosomes to two daughter cells requires unimpaired Plk function. Until recently, aneuploidy, the condition in cancer cells in which they display an abnormal number of chromosomes, was considered a consequence, rather than a cause, of the malignancy. However, recent studies suggest aneuploidy can cause cancer. Centrosomes play a critical role in the maintainance of the integrity of the human genome. Aberrant centrosome structure and aneuploidy are tightly correlated in advanced tumors. The studies proposed here address the molecular events controlled by Plk involving centrosome duplication and initiation of cleavage furrow formation and the potential of Snk to influence these and other events in specific cell types.