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Novel functions of D-type and E-type cyclins in normal and in cancer cells

D 型和 E 型细胞周期蛋白在正常细胞和癌细胞中的新功能

基本信息

批准号：
9886203
负责人：
Peter Sicinski
金额：
$ 43.1万
依托单位：
DANA-FARBER CANCER INST
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：
2016-04-01 至 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9886203
关键词：
Ablation Acute Address Affect Animals Automobile Driving Binding CCNE1 gene CDK2 gene CDK4 gene Cell Cycle Cell Cycle Progression Cell Differentiation process Cell Proliferation Cells Characteristics Complex Cyclin D1 Cyclin-Dependent Kinases Cyclins Down-Regulation G1 Phase Glioblastoma Grant Growth Human Immunocompromised Host In Vitro Injections Knockout Mice Laboratories Literature Maintenance Malignant - descriptor Malignant Neoplasms Malignant neoplasm of brain Mammalian Cell Molecular Molecular Analysis Mus Nervous system structure Neurons Normal Cell Oncogenic Pathway interactions Patients Phenotype Phosphotransferases Play Proliferating Property Proteins Research Role Set protein Substrate Specificity System Teratoma Testing Therapeutic Time Undifferentiated Work blastocyst cancer cell cancer cell differentiation cancer type cell type conditional knockout cyclin G1 design embryonic stem cell in vivo knock-down mouse model neurogenesis novel novel therapeutics overexpression pluripotency programs protein function public health relevance stem cells stem-like cell stemness subcutaneous tool treatment strategy tumor tumorigenesis tumorigenic

项目摘要

DESCRIPTION (provided by applicant): The proliferation of mammalian cells is driven by the core cell cycle machinery. The key components of this machinery are proteins called cyclins, which bind, activate and provide substrate specificity to the cyclin- dependent kinases (CDKs). Cyclin-CDK complexes phosphorylate cellular proteins, thereby driving cell proliferation. Cyclins operating during the G1 phase of the cell cycle (the so-called "G1 cyclins") are of particular importance to the cancer field, as many oncogenic pathways were shown to impinge on these proteins. Two classes of G1 cyclins operate in mammalian cells: D-type (cyclins D1, D2 and D3) and E-type (E1 and E2). D-cyclins activate CDK4 and CDK6, whereas E-cyclins activate mostly CDK2. Cyclin D-CDK4, D-CDK6 and E-CDK2 complexes phosphorylate an overlapping set of proteins; cyclin E-associated kinase is thought to target a broader spectrum of substrates. In the past, our laboratory generated and characterized mice lacking D-type or E-type cyclins. Although these animals displayed focused abnormalities, the majority of cell types proliferated normally or nearly normally in the absence of D-type or E-type cyclins. We ascribed the absence of more profound phenotypes to the overlapping functions of the two G1 cyclin classes. To better understand the in vivo functions of G1 cyclins, we generated conditional quintuple knockout mouse embryonic stem cells. These cells allow us to study the consequences of an acute shutdown of all five G1 cyclins in embryonic stem cells. In the proposed work, we will use this experimental system to study the molecular functions of G1 cyclins. An important part of our research plan are analyses of G1 cyclin functions in mouse and in human cancer cells. We will focus on glioblastoma, the most aggressive and incurable brain cancer. We will investigate the molecular functions of G1 cyclins in this tumor type, using a mouse model of glioblastoma as well as primary patient-derived glioblastoma cells. We will test whether inhibition of G1 cyclin function might represent a therapeutic strategy in this deadly cancer type. We will address the following major issues in our three Specific Aims: In Specific Aim 1, we will study the function of G1 cyclins in embryonic stem cells. In Specific Aim 2, we will investigate the molecular functions of G1 cyclins during differentiation. Lastly, in Specific Aim 3, we will extend our studies to mous and human patient-derived cancer cells, by analyzing the function of G1 cyclins in glioblastoma cells. Our work may suggest novel therapeutic strategies for treatment of glioblastoma. This tumor represents the most aggressive and incurable brain cancer, and the median survival time of the affected patients is currently less than one year.