Role of septins in cytokinetic abscission

脓毒症在细胞分裂中的作用

• 批准号: 9257486
• 负责人: Eva Pauline Karasmanis
• 金额: $ 4.4万
• 依托单位: DREXEL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-01-17 至 2020-01-16
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9257486
• 关键词: Ablation; Advanced Malignant Neoplasm; Affect; Aneuploidy; Area; Breast; Cancer Biology; Cancer Etiology; Cause of Death; Cell division; Cells; Cellular biology; Cessation of life; Chromosome Segregation; Chromosome abnormality; Chromosomes; Colorectal; Complex; Cytokinesis; Data; Defect; Development; Diagnosis; Diffusion; Electron Microscopy; Electron Transport Complex III; Endosomes; Evolution; Excision; Fellowship; Filament; GTP-Binding Proteins; Genomic Instability; Goals; Higher Order Chromatin Structure; Image; Incidence; Lead; Light; Lighting; Link; Malignant Neoplasms; Mammalian Cell; Mammals; Mediating; Medical; Membrane; Mentors; Methods; Microscopy; Mitosis; Outcome; Pathway interactions; Pennsylvania; Platinum; Process; Proteins; Publishing; Recruitment Activity; Regulation; Research; Resolution; Role; Saccharomycetales; Site; Solid Neoplasm; Sorting - Cell Movement; Structure; Testing; Time; Training; Universities; Vesicle; Work; Yeasts; anticancer research; aurora B kinase; base; career; constriction; experimental study; insight; knock-down; light microscopy; molecular assembly/self assembly; overexpression; photoactivation; pre-doctoral; symposium; targeted cancer therapy

Project Summary Cancer remains a leading cause of death worldwide. In the US, there are over 1.5 million new diagnoses and half million deaths annually. Over 90% of solid tumors (e.g., breast, colorectal) are characterized by chromosomal abnormalities including aneuploidy, the loss or gain of chromosomes, which contributes to the genomic instability that drives cancer development. Aneuploidy arises from defects in chromosome segregation during mitosis. In late mitosis, the intercellular bridge (ICB) that connects the two compartments of a dividing cell is severed by a process termed abscission. Abscission provides a mechanism for delaying cell division in the presence of missegregated chromosomes (NoCut checkpoint) that are trapped in the ICB. Thus, defects in abscission and the NoCut checkpoint result in aneuploidy and chromosome damage. Abscission involves the constriction and severing of the ICB membrane by the endocytic sorting complex required for transport-III (ESCRT-III). Assembly of this multi-component membrane complex is spatially and temporally regulated, and requires the targeting and fusion of ESCRT-III-carrying endosomes with the ICB. To date, however, very little is known about of how ESCRT-III assembly is spatio-temporally coordinated with endosome fusion and how it is linked to the NoCut checkpoint. Septins are GTP-binding proteins that are abnormally expressed in many cancers. Septins assemble into higher order structures that control the spatial organization of membrane and cytosolic proteins. In yeast, septins are essential for the spatial coordination of cytokinesis. In mammalian cells, septins are required for the completion of abscission, but their functions are poorly understood. Based on preliminary data, we hypothesize that septins regulate the assembly of the ESCRT-III complex. Here, we will determine how septins function in the recruitment and assembly of ESCRT- III subunits into rings and spiral filaments. We will test for septin roles in the spatial organization of the ESCRT- III complex and the endosomal delivery of its components. Importantly, the proposed work will examine how abnormalities in septin expression, which are common in cancer, affect the NoCut checkpoint. The proposed studies require training in cutting edge methods of light and electron microscopy (EM) including structured illumination super-resolution microscopy and correlative light and platinum replica EM. The overarching goal of this pre-doctoral fellowship project is to prepare for an independent career in the broader areas of cell and cancer biology. In summary, the proposed project will shed new insights into the mechanisms of cytokinetic abscission and septins, which are abnormally expressed in many cancers, but their roles remain poorly understood.

项目摘要 癌症仍然是全球死亡的主要原因。在美国，有超过150万个新诊断和 每年有500万人死亡。超过90％的实体瘤（例如乳房，结直肠瘤）的特征是 染色体异常，包括非整倍性，染色体的损失或增益，这有助于 促进癌症发展的基因组不稳定。非整倍性来自染色体的缺陷 有丝分裂过程中的分离。在晚期有丝分裂中， 连接两个隔室的细胞间桥（ICB） 分隔单元被称为脱落的过程切断。脱落提供了延迟细胞的机制 在冰上捕获的染色体（NOCUT检查点）存在的情况下进行的分裂。因此， 脱落和Nocut检查点的缺陷导致非整倍性和染色体损伤。脱落 涉及通过所需的内吞分选复合物的收缩和切断ICB膜的收缩和切断 运输-III（ESCRT-III）。该多组分膜复合物的组装在空间和时间上是 受调节，需要靶向和融合ESCRT-III携带的内体与ICB。迄今为止， 但是，关于eSCRT-III组装如何与时空协调的eSCRT-III组装知之甚少 内体融合及其如何链接到Nocut检查点。 Septins是GTP结合蛋白 在许多癌症中表达异常。 Septins组装成控制空间的高阶结构 膜和胞质蛋白的组织。在酵母中，Septins对于空间协调至关重要 细胞因子。在哺乳动物的细胞中，脱落完成需要隔两个，但它们的功能是 理解不佳。根据初步数据，我们假设Septins调节了组装 ESCRT-III复合物。在这里，我们将确定septins在招募和组装中的作用 III亚基成环和螺旋细丝。我们将在ESCRT-的空间组织中测试SEPTIN角色 III复合物及其组件的内体递送。重要的是，拟议的工作将研究如何 在癌症中常见的Septin表达异常会影响Nocut检查点。提议 研究需要培训光和电子显微镜（EM）的尖端方法，包括结构化 照明超分辨率显微镜以及相关光和铂副本EM。总体目标 这个博士前的奖学金项目是为在更广泛的牢房和广泛领域做准备 癌症生物学。总而言之，拟议的项目将为细胞动力学的机理提供新的见解 脱落和隔膜，在许多癌症中均异常表达，但它们的作用仍然很差 理解。