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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

基本信息

批准号：
10365189
负责人：
Michael James Emanuele
金额：
$ 31.44万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
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：
2016-09-01 至 2026-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10365189
关键词：
Address Amyotrophic Lateral Sclerosis Apoptosis Attention Binding CRISPR/Cas technology Cell Cycle Cell Cycle Progression Cell Cycle Regulation Cell Line Cells Chromosomal Stability Clinical Complex Cyclin-Dependent Kinase Inhibitor Cyclin-Dependent Kinases Cyclins Data Deubiquitination Disease Enzymes Eukaryota F Box Domain F-Box Proteins Family Funding Gene Expression Genes Genetic Transcription Goals Growth Health Human Human Cell Line Impairment Kinetics Knowledge Ligase Link Malignant Neoplasms Mass Spectrum Analysis Messenger RNA Methodology Mus Mutation Names Neurodegenerative Disorders Normal Cell PLK1 gene Pathway interactions Phenotype Phosphoproteins Phosphorylation Phosphorylation Site Phosphotransferases Play Post-Translational Regulation Process Protein Family Proteins Proteome Proteomics RBL2 gene Regulation Resources Retinoblastoma Role S phase System Textbooks Tumor Suppressor Proteins Ubiquitin Ubiquitin family Ubiquitination Work cdc Genes cyclin F genome integrity genome-wide human disease in silico innovation loss of function member nervous system disorder ovarian neoplasm overexpression programs protein degradation receptor retinoblastoma pathway senescence ubiquitin ligase ubiquitin-protein ligase

项目摘要

PROJECT SUMMARY ABSTRACT Dynamic oscillations in the abundance and activity of key proteins drives cell cycle progression. This is typified by cyclins and cyclin kinase inhibitors (CKIs), which oscillate during cell cycle progression and determine the activation kinetics of Cyclin Dependent Kinases, which propel the cell cycle forward. Defining the pathways, networks and mechanisms underlying dynamics in protein abundance during normal cell cycles is essential to understanding proliferative control. Ubiquitin is the major regulator of protein degradation in eukaryotes and plays an essential and highly conserved role in cell cycle progression. The Skp1-Cul1-F-box (SCF) family of E3 ubiquitin ligases are major regulators of cell cycle progression and sculpt the protein landscape post- translationally to facilitate proliferation. SCF ligases engage a set of ~70 interchangeable substrate receptors termed F-box proteins, which dictate SCF target selection. The eponymous Cyclin F is the founding member of the F-box family and has a cyclin homology domain like that found in the canonical CDK activators. Rather than activate a CDK to promote cell cycle via phosphorylation, cyclin F binds to the SCF, promoting cell cycle through ubiquitination. Cyclin F mRNA and protein levels oscillate significantly during the cell cycle and to a greater extent than other F-box encoding genes. Cyclin F is required for viability in mice and essential for growth/survival in many human cell lines. Further, it is overexpressed in cancer, and its mutation is linked to the neurodegenerative disease amyotrophic lateral sclerosis. Nevertheless, there remain significant knowledge gaps related to what pathways cyclin F controls and how it is regulated. Defining substrates and mechanisms of cyclin F is significant to a fundamental understanding of cell cycle, as well as human health. During the previous funding cycle, our lab identified several cyclin F substrates, highlighting its importance in cell cycle control. Here, we build on that work, defining a new substrate with important roles in normal cell cycle control and with relevance to disease, while also beginning to dissect the complex mechanisms by which cyclin F is controlled. Borne out of innovative, unbiased, computational, and proteomic strategies, our data suggest new, critical roles for cyclin F in cell cycle, and undescribed mechanisms underlying its regulation. In aim 1, we examine the role of cyclin F in G1/S progression through regulation of a tumor suppressor in the retinoblastoma (RB)-pocket protein family, RBL2/p130. We will determine the mechanisms by which cyclin F controls the RB-pathway and how this contributes to gene expression, cell cycle, and proliferative control. In aims 2 and 3, we turn our attention towards mechanisms that converge on cyclin F to regulate its abundance and potentially activity. Aim 2 is focused on the regulation of cyclin F by kinases and how they determine cyclin F stability. In aim 3 we extend this analysis of post-translational regulation of cyclin F, determining how it is regulated by deubiquitinases. Together, these studies will provide a comprehensive analysis for how cyclin F is itself regulated and its contributions to cell cycle in humans.

项目摘要