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Mechanisms of cyclin E associated tumorigenesis

细胞周期蛋白E相关肿瘤发生机制

基本信息

批准号：
7263987
负责人：
Alexander C Minella
金额：
$ 3.3万
依托单位：
FRED HUTCHINSON CANCER RESEARCH CENTER
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-07-01 至 2007-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7263987
关键词：
1-Phosphatidylinositol 3-Kinase Aneuploidy Animals Area Breast Carcinoma Cancer Biology Cell Cycle Cell Cycle Progression Cell Cycle Regulation Cells Centrosome Chromosomal Instability Chromosome Structures Chromosome abnormality Communities Complex Cyclin E Data Development Environment Family member Fred Hutchinson Cancer Research Center Genetic Genome Goals Human Knockout Mice Lymphoma Malignant Neoplasms Maps Mass Spectrum Analysis Mediating Mentors Molecular Mutation Neoplastic Cell Transformation Numbers Oncogenic Pathway interactions Phase Phosphoinositide-3-Kinase, Catalytic, Gamma Polypeptide Phosphopeptides Phosphorylation Phosphotransferases Physicians Physiological Post-Translational Protein Processing Post-Translational Regulation Pre-Replication Complex Principal Investigator Process Protein Overexpression Protein p53 Proteins Regulation Research Research Personnel Research Proposals Scientist Serine Site TP53 gene Testing Thinking Tissues Training Transgenes Transgenic Organisms Tumor Biology Tumor Suppressor Proteins cancer cell career experience in vivo in vivo Model interest mouse model oncoprotein p21 research study response skills tumor tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): Cyclin E, with its partner kinase Cdk2, controls cell cycle progression from G1 to S phase. Most human cancers contain mutations in the major pathway that regulates G1 to S phase progression, and these mutations deregulate cyclin E-Cdk2 activity. Though deregulated cyclin E-Cdk2 activity is thought to contribute directly to neoplastic transformation, the mechanisms connecting cyclin E to tumorigenesis remain unclear. We studied the consequences of cyclin E deregulation in primary cells and unexpectedly found that cyclin E overexpression initiates a homeostatic response that restrains cyclin E-Cdk2 activity. When this response is inactivated, overexpressed cyclin E induces profound cell cycle abnormalities and evidence of genetic instability. Therefore, this response, which requires the p53 tumor suppressor protein and the cyclin dependent kinase inhibitor, p21, protects cells against cyclin E deregulation and may comprise a physiologic barrier against cyclin E associated cancer. The experiments proposed in this application seek to understand the cellular consequences of cyclin E deregulation and the contributions of cyclin E deregulation to tumorigenesis. The goal of Specific Aim 1 is to elucidate the mechanism by which cyclin E activates p53. Excess cyclin E-cdk2 activity induces defective S phase progression and accumulated cytogenetic abnormalities. The goal of Specific Aim 2 is to understand the mechanisms through which cyclin E activity causes genome damage and whether p53 inactivation is an obligatory step in this process. The combination of cyclin E deregulation and p53 loss may be synergistically oncogenic by promoting genetic damage while inactivating the major cellular protective response against this damage. The goal of Specific Aim 3 is thus to determine if cyclin E and p53 loss cooperate during tumorigenesis by developing mouse models of cyclin E associated cancers. The career development goal of this proposal is to enable the principal investigator to acquire the necessary skills to develop a successful and independent research career with interests bridging cell cycle regulation and tumor biology, This proposal is co-mentored by Drs. Bruce Clurman and James Roberts, who have extensive experience studying cell cycle regulation in normal and cancer cells. The Fred Hutchinson Cancer Research Center includes a thriving community of scientists and physicians with expertise in diverse areas of cancer biology and thus provides an ideal training environment for this research proposal.

描述（由申请人提供）：细胞周期蛋白E及其伴侣激酶Cdk 2控制细胞周期从G1期到S期的进程。大多数人类癌症在调节G1至S期进展的主要途径中含有突变，并且这些突变使细胞周期蛋白E-Cdk 2活性失调。尽管细胞周期蛋白E-Cdk 2活性的失调被认为直接促进肿瘤转化，但细胞周期蛋白E与肿瘤发生的机制仍不清楚。我们研究了原代细胞中细胞周期蛋白E失调的后果，意外地发现细胞周期蛋白E过表达启动了一种抑制细胞周期蛋白E-Cdk 2活性的稳态反应。当这种反应失活时，过表达的细胞周期蛋白E诱导深刻的细胞周期异常和遗传不稳定性的证据。因此，这种需要p53肿瘤抑制蛋白和细胞周期蛋白依赖性激酶抑制剂p21的反应保护细胞免受细胞周期蛋白E失调的影响，并可能构成针对细胞周期蛋白E相关癌症的生理屏障。本申请中提出的实验试图理解细胞周期蛋白E失调的细胞后果和细胞周期蛋白E失调对肿瘤发生的贡献。 Specific Aim 1的目标是阐明细胞周期蛋白E激活p53的机制。过量的细胞周期蛋白E-cdk 2活性诱导缺陷的S期进展和累积的细胞遗传学异常。具体目标2的目标是了解细胞周期蛋白E活性导致基因组损伤的机制，以及p53失活是否是这一过程中的必要步骤。细胞周期蛋白E失调和p53缺失的组合可能通过促进遗传损伤同时使针对这种损伤的主要细胞保护性反应失活而协同致癌。因此，特定目标3的目标是通过开发细胞周期蛋白E相关癌症的小鼠模型来确定细胞周期蛋白E和p53损失在肿瘤发生期间是否合作。该提案的职业发展目标是使主要研究者获得必要的技能，以发展成功和独立的研究职业生涯，并对细胞周期调控和肿瘤生物学感兴趣，该提案由布鲁斯Clurman博士和James Roberts博士共同指导，他们在正常细胞和癌细胞的细胞周期调控方面拥有丰富的经验。弗雷德哈钦森癌症研究中心包括一个繁荣的科学家和医生社区，他们在癌症生物学的不同领域拥有专业知识，因此为这项研究提案提供了理想的培训环境。