Regulating centrosome homeostasis through the UPS

通过 UPS 调节中心体稳态

• 批准号: 9178269
• 负责人: MICHELE PAGANO
• 金额: $ 18.43万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9178269
• 关键词: 26S proteasome; Affinity Chromatography; Binding; Binding Proteins; Biochemical; Biological Assay; Biology; Boxing; CUL1 gene; Cancer Biology; Cell Cycle; Cell Cycle Progression; Cell Line; Cell physiology; Cells; Centrioles; Centrosome; Chromosomal Instability; Cilia; Clinical; Complex; Cullin Proteins; Degradation Pathway; Development; Disease; Drug Targeting; Dwarfism; Enzymes; F Box Domain; F-Box Motifs; F-Box Proteins; Family; Grant; Hereditary Disease; Homeostasis; IL27RA gene; Laboratories; Lead; Ligase; Lysine; Malignant Neoplasms; Malignant neoplasm of brain; Mammals; Mass Spectrum Analysis; Mediating; Microcephaly; Molecular; Neurons; Oranges; Orphan; Phase; Phosphorylation; Play; Polyubiquitin; Population Research; Post-Translational Protein Processing; Process; Proteins; Proteolysis; Proteomics; Publishing; Recruitment Activity; Regulation; Research; Research Project Grants; Resources; Role; Signal Transduction Pathway; Specificity; System; Techniques; Thalidomide; Ubiquitin; Ubiquitin-Conjugating Enzymes; Ubiquitin-mediated Proteolysis Pathway; Ubiquitination; base; beta-Transducin Repeat-Containing Proteins; ciliopathy; cyclin F; fight against; genetic regulatory protein; human disease; inhibitor/antagonist; lenalidomide; multicatalytic endopeptidase complex; neurodevelopment; neuron development; novel; programs; protein complex; protein degradation; protein protein interaction; receptor; response; scaffold; ubiquitin ligase; ubiquitin-protein ligase; web-accessible

PROJECT SUMMARY/ABSTRACT Ubiquitin-mediated proteolysis regulates the degradation of numerous proteins, thereby controlling many cellular processes, including cell cycle progression, signal transduction pathways, differentiation, and the centrosome duplication cycle. Much of the specificity inherent in the ubiquitination process is mediated by the E3 ubiquitin ligases, which bind selectively to, and recruit, the chosen substrate to the ubiquitin-conjugating enzyme. Notably, the majority of ubiquitin ligases are considered “orphan”, because their substrates have not yet been identified. Several ubiquitin ligases localize to the centrosome and control the ubiquitination and subsequent proteasomal degradation of critical centriole duplication factors, such as CP110, PLK4, and SAS6 (by SCF-Cyclin F, SCF-βTrCP, and APC/C-Cdh1, respectively). Furthermore, ubiquitin ligases also control additional centrosomal functions, such as centriole separation (through the SCF-βTrCP-mediated degradation of Cep68). Our preliminary results show that additional “orphan” E3 ligase complexes reside at the centrosome, and that several centrosomal proteins are degraded by the ubiquitin system during specific phases of the cell cycle. We propose a project systematically exploring the regulation of the centrosome cycle by the ubiquitin-proteasome system. We will use proteomic techniques to identify novel substrates of centrosomal E3 ligases (specific AIM 1) and will validate and biochemically characterize the most biologically significant substrates identified under AIM 1 (specific AIM 2). We will make our analysis of E3 ubiquitin ligases and centrosome interactors available as a web-accessible resource. Centrosome amplification is a common feature of the large majority of cancers and can result in chromosome instability. Furthermore, centrosome abnormalities are also associated with genetic disorders of neurons and cellular cilia. Therefore, the information gained from the proposed studies is expected to be of direct relevance to our understanding of cancer biology and other human diseases such as ciliopathies and neuronal development disorders.

项目摘要/摘要 泛素介导的蛋白质降解调节多种蛋白质的降解，从而 控制许多细胞过程，包括细胞周期进程、信号转导 途径、分化和中心体复制周期。大部分的特定性 泛素化过程中固有的是由E3泛素连接酶介导的，它结合 选择性地将所选择的底物招募到泛素结合酶。值得注意的是， 大多数泛素连接酶被认为是“孤儿”，因为它们的底物还没有 已被确认身份。几种泛素连接酶定位于中心体并控制 关键中心粒复制因子的泛素化和随后的蛋白酶体降解， 例如CP110、Plk4和SaS6(分别通过SCF-Cyclin F、SCF-βTrCP和APC/C-CDH1)。 此外，泛素连接酶还控制中心粒等额外的中心体功能。 分离(通过SCF-βTrCP介导的Cep68降解)。我们的初步结果 显示另外的孤立的E3连接酶复合体驻留在中心体，以及几个 中心体蛋白在细胞的特定阶段被泛素系统降解。 周而复始。我们提出了一个项目，系统地探索中心体周期的调节，通过 泛素-蛋白酶体系统。我们将使用蛋白质组学技术来鉴定新的 中心体E3连接酶底物(特异性AIM 1)，并将验证和生化 确定AIM 1(特定AIM 2)中确定的最具生物学意义的底物的特征。 我们将把我们对E3泛素连接酶和中心体相互作用的分析作为一种 可通过Web访问的资源。中心体扩增是绝大多数人的共同特征 癌症，并可能导致染色体不稳定。此外，中心体异常是 也与神经元和细胞纤毛的遗传障碍有关。因此，这些信息 从拟议的研究中获得的成果预计将与我们对 癌症生物学和其他人类疾病，如纤毛疾病和神经元发育 精神错乱。