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.

项目概要 癌症仍然是全世界死亡的主要原因。美国新增确诊病例超过 150 万例 每年有五十万人死亡。超过 90% 的实体瘤（例如乳腺癌、结直肠癌）的特征是 染色体异常，包括非整倍体、染色体的丢失或获得，这会导致 驱动癌症发展的基因组不稳定性。非整倍体是由染色体缺陷引起的 有丝分裂期间的分离。在有丝分裂晚期， 连接两个细胞的细胞间桥（ICB） 分裂中的细胞被称为脱落的过程切断。脱落提供了一种延迟细胞分裂的机制 在 ICB 中存在错误分离的染色体（NoCut 检查点）的情况下进行分裂。因此， 脱落缺陷和 NoCut 检查点会导致非整倍体和染色体损伤。脱离 涉及通过内吞分选复合物所需的 ICB 膜的收缩和切断 运输-III (ESCRT-III)。这种多组分膜复合物的组装是在空间和时间上进行的 调节，并且需要携带 ESCRT-III 的内体与 ICB 的靶向和融合。迄今为止， 然而，人们对 ESCRT-III 组装如何与时空协调的了解甚少。 内体融合及其与 NoCut 检查点的联系。 Septin 是 GTP 结合蛋白， 在许多癌症中异常表达。 Septins组装成控制空间的更高阶结构 膜和胞浆蛋白的组织。在酵母中，septin 对于空间协调至关重要 胞质分裂。在哺乳动物细胞中，脓蛋白是完成脱落所必需的，但它们的功能是 不太了解。根据初步数据，我们假设脓蛋白调节 ESRT-III 复合物。在这里，我们将确定脓蛋白在 ESCRT 的招募和组装中如何发挥作用- III亚基分为环和螺旋丝。我们将测试 septin 在 ESCRT 空间组织中的作用- III 复合物及其成分的内体递送。重要的是，拟议的工作将研究如何 septin 表达异常在癌症中很常见，会影响 NoCut 检查点。拟议的 研究需要光学和电子显微镜（EM）尖端方法的培训，包括结构化 照明超分辨率显微镜和相关光和铂复制品电子显微镜。总体目标是 该博士前奖学金项目旨在为细胞和更广泛领域的独立职业做好准备 癌症生物学。总之，拟议的项目将为细胞因子的机制提供新的见解 脱落和脓毒症，在许多癌症中异常表达，但它们的作用仍然很差 明白了。