Ubiquitin-dependent mechanisms of tissue-specific cell cycle control

组织特异性细胞周期控制的泛素依赖性机制

基本信息

批准号：
7431182
负责人：
Michael P Rape
金额：
$ 229.98万
依托单位：
UNIVERSITY OF CALIFORNIA BERKELEY
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-09-30 至 2012-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7431182
关键词：
26S proteasome Accounting Achievement Active Sites Address Adenomatous Polyposis Coli Protein Adverse effects Affect Affinity Affinity Chromatography Aliquot Aneuploidy Animal Model Animals Antimitotic Agents Apoptosis Architecture Attention Automation Autoradiography Award BRCA1 gene Bacteria Binding Biochemical Biochemistry Biological Assay Biology Boston Boxing Breast Breast Cancer Cell Bypass CDC2 Protein Kinase CDKN1A gene Caenorhabditis elegans California Catalytic Domain Cause of Death Cdc25B protein Cell Count Cell Cycle Cell Cycle Arrest Cell Cycle Checkpoint Cell Cycle Deregulation Cell Cycle Progression Cell Cycle Regulation Cell Cycle Stage Cell Extracts Cell Line Cell division Cells Cellular biology Cessation of life Charge Chemicals Cherry - dietary Chromosome Condensation Class Collaborations Colon Colon Carcinoma Complex Condition Conserved Sequence Cultured Cells Cyclin D1 Cyclin E Cyclin-Dependent Kinase Inhibitor Cyclin-Dependent Kinases Cyclins Cysteine Cytokinesis DNA DNA Damage DNA Repair Data Analyses Defect Depth Deubiquitinating Enzyme Deubiquitination Development Developmental Process Differentiation Antigens Dimethyl Sulfoxide Disease Dissection Dominant-Negative Mutation Down-Regulation Drosophila genus Drug Combinations Drug Delivery Systems Elements Embryo Employee Strikes Employment End Point Assay Endocytosis Energy Transfer Environment Enzyme Inhibitor Drugs Enzyme Inhibitors Enzymes Epidermal Growth Factor Receptor Erythropoiesis Essential Genes Esters Ethylmaleimide Eukaryota Eukaryotic Cell Event Failure Family member Figs - dietary Fluorescence Forcible intercourse Gene Expression Genes Genetic Genetic Screening Genetic Transcription Genus Cola Germ-Line Mutation Giant Cells Gleevec Goals Green Fluorescent Proteins Growth Growth Factor Growth Factor Receptors Hela Cells Hematopoiesis Hematopoietic Hereditary Disease Histones Hour Human Human Resources Image Analysis Immunoprecipitation In Vitro Incubated Individual Insecta Institution Interphase Interphase Cell Investigation Knock-out Knockout Mice Knowledge Label Laboratories Lead Left Libraries Life Link Lung Lymphocyte Lysine Malignant Neoplasms Malignant neoplasm of ovary Mammals Masks Mass Spectrum Analysis Measurement Measures Mediating Meiosis Metabolic stress Microarray Analysis Microscope Microtubules Miniaturization Mitosis Mitotic Modeling Modification Monitor Monoubiquitination Morphology Mus Muscle Mutate Mutation Nature Neurons Normal tissue morphology Nuclear Numbers Object Attachment Oncogenes Oncogenic Oocytes Organism Organogenesis Ovarian Paclitaxel Pathway interactions Peptides Pharmaceutical Preparations Phase Phenotype Phosphoric Monoester Hydrolases Phosphorylation Phosphotransferases Point Mutation Problem Solving Process Protein Overexpression Proteins Proteolysis Publications Qualifying Radiolabeled Reaction Reader Recombinant Proteins Recombinants Recruitment Activity Regulation Research Research Design Research Personnel Resistance Retinoblastoma Role Running Science Scientist Score Screening procedure Selection Criteria Serine Signal Pathway Signal Transduction Sirolimus Sister Chromatid Small Interfering RNA Specificity Staining method Stains Sterility Structure Surface System TP53 gene Techniques Testing Therapeutic Time TimeLine Tissues Toxin Transcriptional Activation Transfection Translations Ubiquitin Ubiquitination United States Universities Up-Regulation Week Wing Yeasts abstracting base c-myc Genes cDNA Library cancer cell cell type cellular imaging chemotherapy enzyme mechanism enzyme substrate experience expression cloning fluorophore genetic regulatory protein high throughput screening human CCNE1 protein human PTTG1 protein human disease improved inhibitor/antagonist innovation insight knockout gene medical schools member miniaturize monastrol multicatalytic endopeptidase complex mutant network models novel oncoprotein p21 p27 Cell Cycle Protein p27 Enzyme Inhibitor programs protein degradation radiotracer reconstitution research study roscovitine small hairpin RNA small molecule small molecule libraries thioester tissue/cell culture tool transcription factor trophoblast tumor tumorigenesis ubiquitin ligase wasting wortmannin

项目摘要

This proposal describes an integrated approach to identify modules of tissue-specific cell cycle control. Despite clear evidence for tissue-specificity in proliferation and the outstanding importance of tissue-specific cell cycle regulation for development and disease, the underlying mechanisms have not been uncovered. The identification and characterization of tissue-specific modules in proliferative networks will not only provide deep insight into development of multicellular organisms and tumorigenesis, but also lay the groundwork for the discovery of tissue-specific chemotherapeutics. Because of the crucial role of ubiquitination in cell cycle control, the tissue-specific expression of ubiquitination enzymes, the frequent misregulation of ubiquitination in cancer, and the enzymatic nature of ubiquitination, we will focus the dissection of tissue- specific cell cycle regulation on members of the ubiquitination machinery. Using synthetic lethality siRNA screens in different cell lines, we will identify ubiquitination enzymes required for tissue-specific cell cycle control. By isolating substrates of these enzymes unique to a certain tissue, we will delineate pathways underlying cell cycle regulation in this tissue. Finally, by developing and miniaturizing quantifiable ubiquitination assays, we will isolate small-molecule inhibitors that allow further dissection of proliferative networks and may serve as lead structures for novel tissue-specific chemotherapeutics. We are convinced that this integrated approach using genetic discovery, biochemical dissection, and inhibitor identification based on chemical biology will provide deep insights into cell cycle and developmental regulation and lay the groundwork for novel, innovative chemotherapeutics with improved tissue-specificity.

该提案描述了一种识别组织特异性细胞模块的综合方法循环控制。尽管有明确的证据表明增殖的组织特异性和组织特异性细胞周期调控对于发育和发育具有突出的重要性疾病的发生，其潜在机制尚未被揭示。身份识别和增殖网络中组织特异性模块的表征不仅可以提供深入洞察多细胞生物的发育和肿瘤发生，同时也奠定了为发现组织特异性化疗药物奠定了基础。由于泛素化在细胞周期控制中的关键作用，组织特异性泛素化酶的表达，泛素化的频繁错误调节癌症，以及泛素化的酶性质，我们将重点关注组织的解剖- 对泛素化机制成员的特定细胞周期调节。在不同的细胞系中使用合成致死性 siRNA 筛选，我们将鉴定组织特异性细胞周期控制所需的泛素化酶。通过隔离这些酶的底物是特定组织特有的，我们将描绘出途径该组织中潜在的细胞周期调节。最后，通过开发和小型化可量化的泛素化检测，我们将分离出小分子抑制剂，使进一步剖析增殖网络，并可能作为新的先导结构组织特异性化疗。我们相信，这种利用基因发现、生物化学的综合方法基于化学生物学的解剖和抑制剂鉴定将提供深入的对细胞周期和发育调控的见解，为新颖的、具有改善组织特异性的创新化疗药物。