Molecular Mechanism of the Contractile-Ring Assembly in Fission Yeast Cytokinesis

裂殖酵母细胞分裂中收缩环组装的分子机制

• 批准号: 7778799
• 负责人: Jian-Qiu Wu
• 金额: $ 27.8万
• 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: 2009-04-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7778799
• 关键词: Actinin; Actins; Actomyosin; Animals; Apoptotic; Binding; Biochemical; Biological Models; Bundling; Cell Differentiation process; Cell Proliferation; Cell division; Cell physiology; Cells; Characteristics; Complex; Confocal Microscopy; Contractile System; Cytokinesis; Data; Dependency; Drosophila polo protein; Epithelial; Erythrocytes; Evolution; Figs - dietary; Fimbrin; Fission Yeast; Fluorescence Recovery After Photobleaching; Fluorescence Resonance Energy Transfer; Foundations; Generations; Genetic; Genome; Goals; Human; Learning; Link; Malignant Neoplasms; Maps; Measures; Microfilaments; Microscopic; Molecular; Motor; Muscle; Myosin Regulatory Light Chains; Myosin Type II; Organism; Pathway interactions; Phosphorylation; Physical condensation; Play; Positioning Attribute; Process; Proteins; Reproduction; Research; Resolution; Role; Signal Pathway; Signal Transduction; Signaling Protein; Simulate; Site; Solid; Stem cells; Structural Protein; Structure; Systems Analysis; Testing; Work; Wound Healing; Yeasts; anillin; base; cancer cell; cell type; constriction; crosslink; daughter cell; fungus; human disease; link protein; mutant; protein structure; public health relevance; research study; simulation

DESCRIPTION (provided by applicant): A significant gap exists in understanding the mechanism of contractile-ring assembly during cytokinesis, which partitions cellular constituents into two new daughter cells and plays a crucial role in cell reproduction and cell differentiation. The long-term goal of our research is to investigate cytokinesis in yeast, in normal somatic and stem cells, as well as in cancer cells. The objective of this application is to investigate the molecular mechanism of the assembly of the contractile ring in fission yeast cytokinesis. The fission yeast Schizosaccharomyces pombe has emerged as one of the leading model systems for the analysis of cytokinesis. Not only is it genetically tractable and favorable for microscopic analysis, but it also has the smallest fully sequenced eukaryotic genome and carries out cytokinesis much like animal cells. Contractile rings consisting of actin filaments, myosin-II motors, and >30 other proteins are essential for cytokinesis in both yeast and animal cells, including humans. The majority of these proteins are conserved during evolution. The central hypothesis of this proposal is that the cytokinetic contractile ring assembles progressively at the cleavage site from a broad band of precursor nodes into a complex protein structure. Actin cross-linking proteins and Polo kinase play essential structural and signaling roles during the assembly. Based on a solid foundation of background research and strong preliminary data, this hypothesis will be tested by investigating three specific aims: 1) Elucidate the roles of the anillin Mid1p in node formation and identify its binding partners in the nodes; 2) Establish the roles of actin cross-linking proteins Fimbrin and 1-actinin in coalescing the nodes into the contractile ring; 3) Explore the signaling pathways that trigger node formation and node condensation into the contractile ring. A combination of cellular, genetic, biochemical, and confocal microscopic approaches will be employed in these studies. This research is significant because it will reveal how proteins work together during contractile-ring assembly in cytokinesis, and how the anillin Mid1p initiates the assembly of the contractile ring by interacting with evolutionarily conserved structural and signaling proteins. Discerning the assembly of the essential contractile-ring is an important step towards understanding cytokinesis. Additionally, it will help us understand complex actomyosin contractile systems in other cellular processes. PUBLIC HEALTH RELEVANCE: Uncontrolled and misoriented cell divisions are defining characteristics of cancer. Contractile rings, tiny muscle-like force-producing structures, are the common machinery for cytokinesis and other processes including erythrocyte enucleation, morphogenetic epithelial closure, epithelial wound healing, and apoptotic cell extrusion. Thus, much of what we learned about the evolutionarily conserved proteins in cytokinesis is ultimately relevant and applicable to cancer and other human diseases.

描述（由申请人提供）：在理解细胞因子过程中收缩环组装机理的机理中存在一个显着的差距，该机理将细胞成分分为两个新的子细胞，并在细胞再现和细胞分化中起着至关重要的作用。我们研究的长期目标是研究酵母，正常体细胞和干细胞以及癌细胞中的细胞因子。该应用的目的是研究裂变酵母细胞动物中收缩环组装的分子机制。裂变酵母菌杂种pombe已成为细胞因子分析的主要模型系统之一。它不仅可以在遗传上进行，而且有利于微观分析，而且还具有最小的完全测序的真核基因组，并且像动物细胞一样进行细胞因子。收缩环由肌动蛋白丝，肌球蛋白-II电动机和> 30种其他蛋白质组成，对于包括人类在内的酵母和动物细胞中的细胞因子都是必不可少的。这些蛋白质的大多数在进化过程中是保守的。该提议的中心假设是，细胞动力学收缩环从较大的前体淋巴结逐渐逐渐聚集到复杂的蛋白质结构。肌动蛋白交联蛋白和polo激酶在组装过程中起必不可少的结构和信号传导作用。基于背景研究的扎实基础和强大的初步数据，将通过研究三个具体目的来检验该假设：1）阐明Anillin Mid1p在节点形成中的作用，并确定其结合伙伴在节点中的作用； 2）确定肌动蛋白交联蛋白纤维蛋白和1-肌动蛋白在将节点融合到收缩环中的作用； 3）探索触发节点形成并将节点缩合到收缩环的信号通路。这些研究将采用细胞，遗传，生化和共聚焦微观方法的结合。这项研究很重要，因为它将揭示蛋白在细胞动力学中的收缩环组装过程中如何一起工作，以及如何通过与进化保守的结构和信号蛋白相互作用来启动收缩环的组装。辨别基本收缩环的组装是了解细胞因子的重要一步。此外，它将帮助我们了解其他细胞过程中复杂的肌动蛋白收缩系统。 公共卫生相关性：不受控制的和不良的细胞分裂是癌症的定义特征。收缩环，微小的肌肉样产生的力结构，是细胞因子和其他过程的常见机制，包括红细胞摘除，形态发生上皮闭合，上皮伤口愈合和凋亡细胞挤出。因此，我们了解了细胞动力学中进化保守的蛋白质的许多知识最终是相关的，并且适用于癌症和其他人类疾病。