Mechanisms of cyclin E associated tumorigenesis

细胞周期蛋白E相关肿瘤发生机制

• 批准号: 6917179
• 负责人: Alexander C Minella
• 金额: $ 13.37万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-01 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6917179
• 关键词: DNA damage; biological signal transduction; breast neoplasms; carcinogenesis; cell cycle; cellular oncology; cyclin dependent kinase; cyclins; enzyme activity; genetically modified animals; laboratory mouse; lymphoma; mass spectrometry; neoplasm /cancer genetics; oncoprotein p21; p53 gene /protein; phosphorylation; posttranslational modifications; protein structure function; transfection

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 Cdk2 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，这些突变会解除细胞周期蛋白 E-Cdk2 活性的调节。 尽管细胞周期蛋白 E-Cdk2 活性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，并意外地发现细胞周期蛋白 E 过度表达会启动抑制细胞周期蛋白 E-Cdk2 活性的稳态反应。 当这种反应失活时，过度表达的细胞周期蛋白 E 会诱导严重的细胞周期异常和遗传不稳定的证据。 因此，这种反应需要 p53 肿瘤抑制蛋白和细胞周期蛋白依赖性激酶抑制剂 p21，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旨在了解细胞周期蛋白E失调的细胞后果以及细胞周期蛋白E失调对肿瘤发生的贡献。 具体目标 1 的目标是阐明细胞周期蛋白 E 激活 p53 的机制。 细胞周期蛋白 E-cdk2 过度活性会导致 S 期进展缺陷并累积细胞遗传学异常。 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 失活是否是该过程中的必要步骤。 细胞周期蛋白 E 失调和 p53 缺失的结合可能会促进遗传损伤，同时使针对这种损伤的主要细胞保护反应失活，从而产生协同致癌作用。 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 丢失在肿瘤发生过程中是否协同作用。 该提案的职业发展目标是使主要研究者能够获得必要的技能，以发展成功和独立的研究职业，并在细胞周期调控和肿瘤生物学之间建立兴趣，该提案由 Drs. 共同指导。 Bruce Clurman 和 James Roberts 在研究正常细胞和癌细胞的细胞周期调控方面拥有丰富的经验。 Fred Hutchinson 癌症研究中心拥有一个由在癌症生物学各个领域拥有专业知识的科学家和医生组成的蓬勃发展的社区，从而为该研究计划提供了理想的培训环境。