SCF Ubiquitin Ligases in Cell Cycle Control and Chromosome Stability

SCF 泛素连接在细胞周期控制和染色体稳定性中的作用

• 批准号: 9158827
• 负责人: Michael James Emanuele
• 金额: $ 30.18万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9158827
• 关键词: Aging; Binding; Biochemistry; Cell Cycle; Cell Cycle Progression; Cell Cycle Regulation; Cell Proliferation; Cell division; Cell physiology; Cells; Chromosomal Stability; Chromosome Segregation; Complex; Cues; Cullin Proteins; Cyclins; Data; Development; Disease; Ensure; Enzymes; F Box Domain; F-Box Proteins; Family; Feedback; Functional disorder; Future; Genetic Materials; Genome; Genome Stability; Growth; Homeostasis; Human; IL27RA gene; Individual; Ligase; Link; Maintenance; Malignant Neoplasms; Maps; Mediating; Mitosis; Mitotic; Molecular; Molecular Mechanisms of Action; Neurodegenerative Disorders; Pathway interactions; Phosphorylation; Phosphotransferases; Play; Positioning Attribute; Post-Translational Protein Processing; Proteins; Proteomics; Proto-Oncogene Protein c-kit; Proto-Oncogene Proteins c-akt; Regulation; Role; S Phase; SKP Cullin F-Box Protein Ligases; Signal Pathway; Signal Transduction; Specific qualifier value; Specificity; System; Systems Biology; TP53 gene; Technical Expertise; Technology; Time; To specify; Tumor Suppression; Tumor Suppressor Proteins; Ubiquitin; Ubiquitin Like Proteins; Validation; base; cyclin F; enzyme substrate; experience; follow-up; human disease; innovation; innovative technologies; insight; interest; multicatalytic endopeptidase complex; novel; overexpression; protein degradation; receptor; transcription factor; ubiquitin-protein ligase

PROJECT SUMMARY ABSTRACT Targeted protein degradation controlled by the ubiquitin proteasome system is involved in virtually all aspects of cellular physiology, including development, signal transduction and aging. In addition, dysfunction in ubiquitin mediated protein degradation is causative in diseases ranging from cancer to neurodegenerative disorders. E3 ligases impart selectivity on the ubiquitin system by specifying target proteins for ubiquitylation and degradation. The Cullin RING E3 ligases (CRLs) represent the largest E3 family in humans. CRLs rely on large families of substrate receptors to specify which substrates become ubiquitylated. Connecting E3 ligases with their cognate substrates, akin to mapping kinase and transcription factor targets, represents the key challenge to defining the function of specific enzymes, and provides mechanistic insight into the role of individual enzymes in cellular homeostasis and disease. The Cullin ligase SCF/CRL1 utilizes a family of 69 substrate receptors termed F-box proteins. The SCF is essential for cell cycle progression, checkpoint function and genome stability. This proposal is focused on Cyclin F, a cell cycle regulated substrate receptor, F-box protein for the SCF. Using Cyclin F as a paradigm, we will interrogate the broader role of CRLs in cell cycle control. By leveraging our expertise in biochemistry, cell and systems biology we will gain a deep understanding of Cyclin F function, and by extension the CRLs, in cell proliferation and genome stability, and its potential contribution to malignancies.

项目摘要 由泛素蛋白酶体系统控制的靶向蛋白质降解几乎涉及所有方面 包括发育、信号转导和衰老。此外， 泛素介导的蛋白质降解是从癌症到神经退行性疾病的病因 紊乱E3连接酶通过指定泛素化的靶蛋白而赋予泛素系统选择性 和退化。Cullin RING E3连接酶（CRL）是人类中最大的E3家族。CRL依赖于 底物受体的大家族，以指定哪些底物变得泛素化。连接E3连接酶 与它们的同源底物，类似于映射激酶和转录因子靶，代表了关键 挑战，以确定特定酶的功能，并提供了机械洞察的作用， 细胞内稳态和疾病中的单个酶。Cullin连接酶SCF/CRL 1利用一个69个 底物受体称为F盒蛋白。SCF对细胞周期进程、检查点功能 和基因组稳定性。该提案的重点是细胞周期蛋白F，一种细胞周期调节底物受体，F-box SCF的蛋白质。以细胞周期蛋白F为范例，我们将探讨CRL在细胞周期中更广泛的作用 控制通过利用我们在生物化学，细胞和系统生物学方面的专业知识，我们将获得深入的 理解细胞周期蛋白F的功能，并通过扩展CRL，在细胞增殖和基因组稳定性， 它对恶性肿瘤的潜在贡献。