Regulating centrosome homeostasis through the UPS

通过 UPS 调节中心体稳态

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/摘要泛素介导的蛋白水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。泛素化过程中固有的现象是由 E3 泛素连接酶介导的，它结合选择性地将选定的底物招募到泛素结合酶中。大多数泛素连接酶被认为是“孤儿”，因为它们的底物尚未已鉴定出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（分别由 SCF-Cyclin F、SCF-βTrCP 和 APC/C-Cdh1 实现）。此外，泛素连接酶还控制其他中心体功能，例如中心粒分离（通过 SCF-βTrCP 介导的 Cep68 降解）。表明额外的“孤儿”E3 连接酶复合物位于中心体，并且几个中心体蛋白在细胞的特定阶段被泛素系统降解我们提出了一个系统地探索中心体循环调节的项目。我们将使用蛋白质组学技术来鉴定新的泛素-蛋白酶体系统。中心体 E3 连接酶的底物（特定 AIM 1），并将进行生化验证描述 AIM 1（特定 AIM 2）下确定的最具生物学意义的底物的特征。我们将对 E3 泛素连接酶和中心体相互作用子的分析作为网络可访问的资源。中心体扩增是大多数的共同特征。癌症并可能导致染色体不稳定。此外，中心体异常也是如此。因此，该信息还与神经元和细胞纤毛的遗传疾病有关。从拟议的研究中获得的成果预计将与我们的理解直接相关癌症生物学和其他人类疾病，例如纤毛病和神经元发育失调。