The role of the NIMA kinase in mitotic regulation

描述(由申请人提供)：有丝分裂调控对所有真核生物的生命至关重要，并具有医学意义，因为有丝分裂缺陷会导致非整倍体和癌症。有丝分裂受一系列保守的蛋白激酶的复杂相互作用的调节，但对相关的激酶底物及其磷酸化的机制后果的了解有限。例如，在开放的有丝分裂过程中，有丝分裂酶是如何调节核孔复合体(NPC)的逐步分解和重组的，目前还不清楚。我的实验室已经证明，在模式丝状真菌nidulans的闭合有丝分裂过程中，NPC被部分分解，至少12个NPC蛋白(NUP)从核心NPC结构可逆地分散开来。因此，核假单胞菌代表了一种独特而强大的模型遗传系统，其中NPC在有丝分裂期间受到调控，其方式与人类有丝分裂NPC的调控方式有许多相似之处。有趣的是，根结线虫An-Nup2仅重新定位到有丝分裂染色体上，这表明该Nup具有新的有丝分裂作用。这一建议旨在：1)详细定义有丝分裂过程中鼻咽癌组成的可逆变化；2)表征鼻咽癌在分解和组装时的结构变化，并将其与鼻咽癌的组成和功能联系起来；3)建立有丝分裂特异性磷酸化如何调节鼻咽癌的结构和功能；以及4)确定an-Nup2在染色质上的定位如何帮助协调鼻咽癌的拆解/重组和有丝分裂的进展。这些研究将有助于确定NPC在有丝分裂过程中如何受激酶的调节，以及NUP的有丝分裂调节如何与有丝分裂进程相结合。

DESCRIPTION (provided by applicant): Mitotic regulation is fundamentally important to all eukaryotic life and has medical significance as mitotic defects can lead to aneuploidy and cancer. Mitosis is regulated by a complex interplay of conserved protein kinases but there is a limited understanding of the pertinent kinase substrates and the mechanistic consequences of their phosphorylation. For example, it is unknown how mitotic kinases regulate the stepwise disassembly and reassembly of the nuclear pore complex (NPC) during open mitosis. My laboratory has shown that during the closed mitosis of the model filamentous fungus Aspergillus nidulans, the NPC is partially disassembled with at least 12 NPC proteins (Nups) reversibly dispersing from a core NPC structure. A. nidulans therefore represents a unique and powerful model genetic system in which the NPC is regulated during mitosis in a manner displaying many similarities to human mitotic NPC regulation. Interestingly, A. nidulans An-Nup2 exclusively re-locates to mitotic chromosomes, suggesting a novel mitotic role for this Nup. This proposal aims to: i) Define in detail the reversible changes in the composition of the NPC during mitosis, ii) Characterize how NPC architecture changes when it is disassembled and assembled and relate this to NPC composition and function, iii) Establish how mitotic specific phosphorylation regulates the structure and function of the NPC, and iv) Determine how the localization of An-Nup2 to chromatin helps coordinate NPC disassembly/reassembly with mitotic progression. These studies will help define how the NPC is regulated by kinases during mitosis and how the mitotic regulation of Nups is integrated with mitotic progression.