Dissecting the role of Aurora A kinase in patterning the cell cortex during cytokinesis.

剖析 Aurora A 激酶在胞质分裂过程中细胞皮质模式化中的作用。

• 批准号: 10387229
• 负责人: Aleesa Schlientz
• 金额: $ 6.72万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10387229
• 关键词: Actins; Actomyosin; Address; Anaphase; Animals; Biological Assay; Biological Models; Caenorhabditis elegans; Cell division; Cell membrane; Cells; Chromosomes; Cleaved cell; Clinical Trials; Cytokinesis; Development; Dimensions; Embryo; Ensure; Failure; Genetic Materials; Human; Lead; Location; Malignant Neoplasms; Mediating; Microtubules; Mitosis; Mitotic; Molecular; Monitor; Mothers; Motor; Mutation; Myosin Type II; Pattern; Phosphotransferases; Positioning Attribute; Process; Proteins; Research; Role; Signal Transduction; Site; Techniques; Testing; Therapeutic; To specify; Up-Regulation; Work; anillin; assay development; aurora kinase A; base; blebbistatin; cancer type; cell cortex; chemotherapeutic agent; chemotherapy; constriction; daughter cell; experimental study; inhibitor; insight; interest; overexpression; tumorigenesis

PROJECT SUMMARY/ABSTRACT Cytokinesis is the final step in mitosis and facilitates the physical cleavage of one cell into two daughter cells. Animal cells achieve cytokinesis through the constriction of a cortical actomyosin contractile ring that forms around the cell equator between the segregating chromosomes. Failure of cytokinesis can lead to the formation of tetraploid cells that are thought to be an important intermediate in tumorigenesis. To ensure equal partitioning of the genetic material, contractile ring assembly is controlled by the anaphase spindle. The anaphase spindle sends two superimposed signals that pattern the contractility of the overlying cortex; a signal from the central spindle that forms between the separating chromosomes promotes contractility of the equatorial cortex, and a signal from the centrosomal microtubule asters suppresses contractility of the non-equatorial cortex. Recent work in C. elegans in my sponsor lab has implicated the mitotic kinase Aurora A in suppressing the accumulation of contractile ring proteins on the non-equatorial cortex. However, whether this function of Aurora A is conserved in human cells and the identity of the Aurora A target sites that mediate suppression of cortical contractility are currently unknown. In the proposed work, I will determine whether the role of Aurora A in patterning cortical contractility is conserved in human cells, use molecular replacement techniques in C. elegans to identify the targets of Aurora A-mediated suppression of cortical contractility, and determine how Aurora A suppression of contractility is integrated with central spindle promotion of contractility to pattern contractile ring formation. In Aim1, I will develop an assay to monitor the suppression of contractility on the non-equatorial cortex during cytokinesis in human cells and use it to determine if Aurora A has a conserved role in this process and whether ectopic targeting of Aurora A to the plasma membrane can suppress contractility. In Aim 2A, I will capitalize on the advantages the C. elegans embryo offers for molecular replacement experiments to perform an unbiased screen of cytokinesis regulators to identify the Aurora A target sites that mediate the ability of centrosomal asters to suppress cortical contractility and will test identified regulatory sites in human cells for conservation. In Aim 2B I will determine how Aurora A and central spindle-derived signals are integrated to allow for the precise specification of contractile ring location and dimensions. Collectively, this work will provide crucial insight into how Aurora A contributes to patterning cortical contractility in dividing cells. As inhibitors targeting Aurora A are currently in clinical trials as potential chemotherapeutic agents, understanding how the role of Aurora A in regulating contractility is related to its functions in tumorigenesis has the potential to impact therapeutic strategies in cancer.

项目摘要/摘要 细胞因子是有丝分裂的最后一步，并促进了一个细胞的物理裂解 子细胞。动物细胞通过皮质肌动蛋白的收缩实现细胞因子 收缩环在分离染色体之间形成细胞赤道周围的收缩环。失败 细胞因子可以导致形成四倍体细胞，被认为是重要的中间体 在肿瘤发生。为了确保遗传物质的平等分配，收缩环组件为 由后期主轴控制。后期主轴发送两个叠加信号，这些信号 对上覆的皮质的收缩性进行模式；来自中央主轴的信号在 分离染色体可促进赤道皮质的收缩性，并从 中心体微管紫外线抑制非赤道皮质的收缩力。最近的工作 我的赞助商实验室中的秀丽隐杆线牵涉到有丝分裂激酶Aurora a抑制 收缩环蛋白在非赤道皮质上的积累。但是，这是否功能 Aurora A的A a aurora a在人类细胞中是保守的，并且Aurora A的身份A靶位位点介导 目前尚不清楚皮质收缩性的抑制。在拟议的工作中，我将确定 Aurora A在模式性皮质收缩力中的作用是否在人类细胞中保守，使用 秀丽隐杆线虫中的分子替代技术，以识别Aurora A介导的目标 抑制皮质收缩力，并确定aurora的收缩力如何抑制 与中央主轴促进收缩力促进图案收缩环形成。在AIM1中，我 将开发一种测定法以监测在非供应皮质上抑制收缩力 人类细胞中的细胞因子并使用它来确定Aurora A在此过程中是否具有保守的作用，并且 Aurora A对质膜的异位靶向是否可以抑制收缩力。在AIM 2A中， 我将利用秀丽隐杆线虫胚胎提供分子替代实验的优势 进行细胞因子调节剂的无偏屏幕以识别介导的Aurora A目标位点 中心紫色抑制皮质收缩力的能力并将测试确定的调节位点 在人类细胞中进行保护。在AIM 2B中，我将确定Aurora A和中央纺锤如何衍生 集成信号以允许收缩环位置和尺寸的精确规范。 总的来说，这项工作将为Aurora A如何促进皮质构造，从而提供重要的见解。 分裂细胞的收缩力。由于针对Aurora A的抑制剂目前正在临床试验中作为潜力 化学治疗剂，了解极光A在调节收缩力中的作用如何相关 它在肿瘤发生中的作用具有影响癌症治疗策略的潜力。