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: 7507083
• 负责人: Michael A Glotzer
• 金额: $ 29.66万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-01 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7507083
• 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; Localized; Malignant Neoplasms; Measures; Mediating; Microtubule Bundle; Microtubules; Mitotic spindle; Molecular; Monomeric GTP-Binding Proteins; Myosin ATPase; Nucleotides; Pathway interactions; Phosphorylation; Positioning Attribute; Process; Proteins; Public Health; Rate; Regulation; Relative (related person); Research Project Grants; Resolution; Scaffolding Protein; Signal Transduction; Site; Stem cells; Structure; Work; anillin; base; cell cortex; cell motility; cell type; cellular imaging; daughter cell; density; improved; insight; multidisciplinary; mutant; novel; nuclear division; rho; rho GTPase-activating protein; rhotekin; 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分裂平面的定位，以便将隔离的染色体组合成干净地分配到两个单独的单元中。此外，在某些细胞类型（包括干细胞）中，必须与局部细胞命运决定因素协调分裂平面。分裂平面定位中的误差会导致染色体增益或损失，细胞命运决定因素的错误分析或细胞因子失败，所有这些都可以加速肿瘤的形成。在后生动物中，分裂平面由后期期间有丝分裂主轴的位置确定。我们发现，两条途径冗余地起作用以定位划分平面。一个途径涉及中央主轴，第二个途径涉及星体微管。这两种途径在机械上和遗传上是不同的。为了了解这些基于微管的结构调节基于肌动菌素的收缩环的形成的机制，我们将使用多学科策略，将秀丽隐杆线虫胚胎和人类细胞中的遗传和细胞生物分析与生物化学和活细胞成像相结合。我们将解决以下问题：将Rhogef ECT2募集到中央主轴上如何导致Rhoa的局部激活？细胞动力学支架蛋白anillin是否调节活性RhoA的水平，新型蛋白质NOP-1如何介导收缩环成分的组织？高微管密度通过什么分子机制抑制肌球蛋白的皮质募集？这些问题的答案将提供有关细胞分裂机理和其他生物学过程的见解，这些过程涉及Rho GTPases的局部调节细胞骨架元素，例如细胞极化和细胞迁移。公共卫生相关性：该项目致力于了解细胞如何繁殖，从而导致两个具有适当细胞嫁妆的子细胞产生。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，并可以识别抗肿瘤疗法的靶标。