The role of the NIMA kinase in mitotic regulation

NIMA 激酶在有丝分裂调节中的作用

• 批准号: 7911004
• 负责人: STEPHEN A OSMANI
• 金额: $ 25.25万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-07 至 2011-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7911004
• 关键词: Address; Affect; Alleles; Aneuploidy; Architecture; Arts; Aspergillus nidulans; Back; Cell Cycle; Chromatin; Chromosomes; Complex; Defect; Diffusion; Dominant-Negative Mutation; Ectopic Expression; Electron Microscopy; Genetic Models; Human; Interphase; Interphase Cell; Laboratories; Lead; Life; Location; Malignant Neoplasms; Mammalian Cell; Maps; Medical; Mitosis; Mitotic; Mitotic Chromosome; Modeling; Molds; NIMA; Nuclear Pore Complex; Nuclear Pore Complex Proteins; Phosphorylation; Phosphorylation Site; Phosphotransferases; Play; Protein Kinase; Regulation; Role; Structure; System; Temperature; Testing; Yeasts; base; deletion analysis; innovation; novel; research study

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.

描述（由申请人提供）：有丝分裂调节对于所有真核生物至关重要，并且具有医学意义，因为有丝分裂缺陷可导致非整倍体和癌症。有丝分裂受到保守蛋白激酶复杂相互作用的调节，但对相关激酶底物及其磷酸化的机制后果的了解有限。例如，尚不清楚有丝分裂激酶如何在开放有丝分裂过程中调节核孔复合体（NPC）的逐步分解和重组。我的实验室表明，在模型丝状真菌构巢曲霉的闭合有丝分裂过程中，NPC 被部分分解，至少有 12 个 NPC 蛋白 (Nups) 从核心 NPC 结构中可逆地分散。因此，A. nidulans 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节，其方式与人类有丝分裂 NPC 调节有许多相似之处。有趣的是，构巢曲霉 An-Nup2 专门重新定位到有丝分裂染色体，表明该 Nup 具有新的有丝分裂作用。该提案的目的是：i) 详细定义有丝分裂期间 NPC 组成的可逆变化，ii) 描述 NPC 结构在拆卸和组装时如何变化，并将其与 NPC 组成和功能联系起来，iii) 确定有丝分裂特异性磷酸化如何调节 NPC 的结构和功能，以及 iv) 确定 An-Nup2 在染色质上的定位如何帮助协调 NPC 拆卸/重组伴随有丝分裂进展。这些研究将有助于确定 NPC 在有丝分裂过程中如何受到激酶的调节，以及 Nups 的有丝分裂调节如何与有丝分裂进展相结合。