Positioning the plane of cell division during cytokinesis

在胞质分裂期间定位细胞分裂平面

• 批准号: 8121346
• 负责人: Michael A Glotzer
• 金额: $ 9.1万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-30 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8121346
• 关键词: Actins; Actomyosin; Address; Anaphase; Aneuploidy; Area; Biochemistry; Biological; Biological Process; Caenorhabditis elegans; Cell Nucleus; Cell division; Cells; Chromosomes; Complex; Contractile Proteins; Coupled; Cytokinesis; Cytoskeleton; Daughter; Dowries; Elements; Embryo; Event; Failure; Family; Family member; Generations; Genetic; Goals; Guanine Nucleotides; Guanosine Triphosphate Phosphohydrolases; Human; Hydrolysis; Lead; Life; Malignant Neoplasms; Measures; Mediating; Microtubule Bundle; Microtubules; Mitotic spindle; Molecular; Monomeric GTP-Binding Proteins; Myosin ATPase; Nucleotides; Pathway interactions; Phosphorylation; Positioning Attribute; Process; Proteins; Regulation; Relative (related person); Research Project Grants; Resolution; Scaffolding Protein; Signal Transduction; Site; Structure; Work; anillin; base; cell cortex; cell motility; cell type; cellular imaging; daughter cell; density; improved; insight; multidisciplinary; mutant; novel; nuclear division; public health relevance; rho; rho GTPase-activating protein; rhotekin; stem cell division; tumor

DESCRIPTION (provided by applicant): Successful cell division requires positioning of the division plane so that the segregated sets of chromosomes are cleanly partitioned into two separate cells. Furthermore, in some cell types, including stem cells, the division plane must be coordinated with localized cell fate determinants. Errors in division plane positioning can cause chromosome gain or loss, missegregation of cell fate determinants, or a failure of cytokinesis, all of which can accelerate tumor formation. In metazoans, the division plane is determined by the position of the mitotic spindle during anaphase. We have found that two pathways act redundantly and cooperatively to position the division plane. One pathway involves the central spindle and the second involves astral microtubules. The two pathways have been demonstrated to be mechanistically and genetically distinct. To understand the mechanism by which these microtubule-based structures regulate formation of a properly positioned actomyosin-based contractile ring, we will use a multidisciplinary strategy, combining genetic and cell biological analysis in C. elegans embryos and human cells, with biochemistry and live cell imaging. We will address the following questions: How does recruitment of the RhoGEF ECT2 to the central spindle result in local activation of RhoA? Does the cytokinetic scaffold protein anillin modulate the levels of active RhoA and how does the novel protein NOP-1 mediate the organization of contractile ring components? Through what molecular mechanism does high microtubule density inhibit cortical recruitment of myosin? The answers to these questions will provide insights into the mechanism of cell division and other biological processes that involve local regulation of cytoskeletal elements by Rho family of GTPases, such as cell polarization and cell migration. PUBLIC HEALTH RELEVANCE: This project is directed towards understanding how cells multiply, leading to the generation of two daughter cells with appropriate cellular dowries. Progress in this area could improve our understanding of how certain cancers develop and could identify targets for anti-tumor therapies.

描述（由申请人提供）：成功的细胞分裂需要定位分裂平面，以便将分离的染色体组干净地划分为两个单独的细胞。此外，在某些细胞类型中，包括干细胞，分裂平面必须与局部细胞命运决定因素协调。分裂平面定位的错误可导致染色体获得或丢失、细胞命运决定因子的错误分离或胞质分裂的失败，所有这些都可加速肿瘤形成。在后生动物中，分裂平面由有丝分裂后期纺锤体的位置决定。我们已经发现，这两个途径的行为冗余和合作，以定位分裂平面。一个途径涉及中央纺锤体，第二个涉及星形微管。这两种途径已被证明是不同的机制和遗传。为了了解这些微管结构调节正确定位的肌动球蛋白收缩环形成的机制，我们将采用多学科策略，结合遗传学和细胞生物学分析，在C.线虫胚胎和人类细胞，生物化学和活细胞成像。我们将解决以下问题：如何招聘的RhoGEF ECT 2的中央纺锤体导致局部激活RhoA？细胞动力学支架蛋白苯胺调节活性RhoA的水平吗？新蛋白NOP-1如何介导收缩环组分的组织化？高微管密度通过何种分子机制抑制皮质肌球蛋白的募集？这些问题的答案将有助于深入了解细胞分裂和其他生物学过程的机制，这些过程涉及Rho家族的GTP酶对细胞骨架元件的局部调节，如细胞极化和细胞迁移。公共卫生相关性：该项目旨在了解细胞如何繁殖，从而产生两个具有适当细胞嫁妆的子细胞。这一领域的进展可以提高我们对某些癌症如何发展的理解，并可以确定抗肿瘤治疗的靶点。