Cytokinesis and the Cytoskeleton in C. elegans Embryos

线虫胚胎中的细胞分裂和细胞骨架

• 批准号: 7618694
• 负责人: BRUCE A BOWERMAN
• 金额: $ 32.58万
• 依托单位: UNIVERSITY OF OREGON
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-05-01 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7618694
• 关键词: Adaptor Signaling Protein; Caenorhabditis elegans; Cell Cycle Progression; Cell division; Collaborations; Collection; Complex; Cytokinesis; Cytoskeleton; Defect; Embryo; Failure; Family; Fertilization; Genes; Genetic Screening; Investigation; Malignant Neoplasms; Mediating; Meiosis; Microfilaments; Microtubules; Mitosis; Mitotic spindle; Molecular Genetics; Neurodegenerative Disorders; Processed Genes; RNA Interference; Regulation; Research; Saccharomycetales; Specificity; Switzerland; Ubiquitin; Ubiquitin-mediated Proteolysis Pathway; base; chromokinesin; human disease; improved; insight; katanin; member; mutant; novel; scaffold; ubiquitin-protein ligase

DESCRIPTION (provided by applicant): Progress on our specific aims over the past four years has led to our discovery of a novel and conserved class of ubiquitin E3 ligases that targets a subunit of the microtubule-severing complex called katanin for ubiquitin-mediated proteolytic degradation, shortly after the completion of meiosis. Katanin is required for meiosis; its subsequent degradation is required for the proper assembly of mitotic spindles, and for the regulation of cortical microfilament contractility during cytokinesis. Thus in addition to influencing regulators of cell cycle progression, we have shown that ubiquitin-mediated proteolysis also influences the cell division machinery itself. Importantly, the E3 ligase we discovered is the founding member of a new class of Cullin- based E3 ligases, composed of a Cullin3 scaffold and one of a large and conserved family of novel adaptor proteins. This finding greatly extends our understanding of the full range of ubiquitin E3 target specificity, and we also have provided new insights into the regulation of E3 ligases. Finally, from extensive screens for conditional mutants with cell division defects, we have identified (i) a chromokinesin, and three additional mutants, that influence central spindle assembly or stability, and the completion of cytokinesis, and (ii) a large collection of meiosis-defective mutants. Our new aims seek to improve our understanding of cytokinesis and meiosis through a molecular genetic investigation of these new mutants. We also will continue our efforts to identify factors that influence E3 ligase function and katanin degradation, in an ongoing collaboration with Dr. Matthias Peter at the ETH in Zurich, Switzerland. The processes and genes we propose to investigate are relevant to important human diseases, including cancer and neurodegenerative disease.

描述（由申请人提供）：过去四年来，我们在具体目标上取得的进展使我们发现了一类新颖且保守的泛素 E3 连接酶，其靶向微管切断复合体的一个亚基（称为剑肽），用于泛素介导的蛋白水解降解，减数分裂完成后不久。 Katanin 是减数分裂所必需的；它随后的降解对于有丝分裂纺锤体的正确组装以及胞质分裂期间皮质微丝收缩性的调节是必需的。因此，除了影响细胞周期进程的调节因子之外，我们还发现泛素介导的蛋白水解也会影响细胞分裂机制本身。重要的是，我们发现的 E3 连接酶是一类新的基于 Cullin 的 E3 连接酶的创始成员，该连接酶由 Cullin3 支架和一个大型保守的新型接头蛋白家族之一组成。这一发现极大地扩展了我们对泛素 E3 靶点特异性的全方位理解，同时也为 E3 连接酶的调控提供了新的见解。最后，通过对具有细胞分裂缺陷的条件突变体的广泛筛选，我们鉴定了（i）一种染色激肽和三个其他突变体，它们影响中央纺锤体组装或稳定性以及胞质分裂的完成，以及（ii）大量减数分裂- 有缺陷的突变体。我们的新目标旨在通过对这些新突变体的分子遗传学研究来提高我们对胞质分裂和减数分裂的理解。我们还将与瑞士苏黎世联邦理工学院的 Matthias Peter 博士持续合作，继续努力确定影响 E3 连接酶功能和剑蛋白降解的因素。我们建议研究的过程和基因与重要的人类疾病相关，包括癌症和神经退行性疾病。