The role of Cyclin E in growth control and tumorogenesis

Cyclin E 在生长控制和肿瘤发生中的作用

• 批准号: 8787588
• 负责人: Steven I Reed
• 金额: $ 9万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-01-01 至 2014-07-24
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8787588
• 关键词: Address; Aneuploidy; Biological; Cancer Biology; Cell Culture Techniques; Cell Cycle Progression; Cells; Complex; Cyclin E; DNA Damage; Defect; Development; Disease; F-Box Proteins; G0 Phase; Genomic Instability; Growth; Health; Human; In Vitro; Investigation; Lead; Link; Loss of Heterozygosity; Malignant Neoplasms; Mammalian Cell; Mediating; Mitosis; Modeling; Molecular; Mus; Oncogene Proteins; Pathway interactions; Phase Transition; Pre-Replication Complex; Process; Proliferating; Proteins; Proteomics; Role; S Phase; Testing; Tissues; Transgenes; Transgenic Mice; Tumor Suppressor Proteins; Ubiquitin; Ubiquitin-mediated Proteolysis Pathway; Work; cancer prevention; cancer therapy; cancer type; carcinogenesis; design; human CCNE1 protein; human CDK2 protein; in vivo; insight; mouse model; novel strategies; overexpression; research study; tumorigenesis; ubiquitin ligase

DESCRIPTION (provided by applicant): Cyclin E, an activator of cyclin-dependent kinase 2 (Cdk2) is a positive activator of the G1-S phase transition in proliferating mammalian cells and therefore serves an important function during development and in replenishment of tissues. However, cyclin E is frequently overexpressed and deregulated in human malignancies, indicating that excessive or mistimed cyclin E-Cdk2 activation can promote oncogenesis. Yet little is known about the normal or pathological functions of cyclin E at the cellular or molecular level. This proposal seeks to investigate both functions of cyclin E through a variety of in vitro and in vivo approaches. The first aim of the proposal focuses on the roles of cyclin E in promoting entry of cells into S phase. Standard molecular and cell biological approaches will be employed. We have also embarked on a proteomic strategy to identify new proteins relevant to the S- phase promoting function of cyclin E. The second aim utilizes cell and molecular biological approaches to elucidate the mechanism(s) whereby cyclin E deregulation causes DNA damage and genomic instability, the most likely link to oncogenesis. In the third aim, cyclin E transgenic mouse carcinogenesis models are used to test the hypothesis of cyclin E- mediated genomic instability in vivo. This is critical, as most prior work has been carried out in cell culture models, which have only a limited relevance to human cancer. Finally, we are investigating the mechanism of cyclin E turnover, since cyclin E becomes deregulated when this process fails. Interestingly, the pathway that targets cyclin E for ubiquitin-mediated proteolysis also targets several other oncoproteins, underscoring its importance for oncogenesis. It is hoped that insights gained from understanding these fundamental mechanisms of oncogenesis will lead to new approaches to cancer prevention and therapy.

描述（由申请人提供）： 细胞周期蛋白 E 是细胞周期蛋白依赖性激酶 2 (Cdk2) 的激活剂，是增殖哺乳动物细胞中 G1-S 相变的正激活剂，因此在发育和组织补充过程中发挥着重要作用。然而，细胞周期蛋白 E 在人类恶性肿瘤中经常过度表达和失调，表明细胞周期蛋白 E-Cdk2 过度或不合时宜的激活可促进肿瘤发生。然而，人们对细胞周期蛋白 E 在细胞或分子水平上的正常或病理功能知之甚少。该提案旨在通过各种体外和体内方法研究细胞周期蛋白 E 的两种功能。该提案的第一个目标集中于细胞周期蛋白 E 在促进细胞进入 S 期中的作用。将采用标准分子和细胞生物学方法。我们还开始采用蛋白质组学策略来鉴定与细胞周期蛋白 E 的 S 期促进功能相关的新蛋白质。第二个目标是利用细胞和分子生物学方法来阐明细胞周期蛋白 E 失调导致 DNA 损伤和基因组不稳定的机制，这最有可能与肿瘤发生有关。第三个目标是使用细胞周期蛋白 E 转基因小鼠致癌模型来测试细胞周期蛋白 E 介导的体内基因组不稳定性的假设。这一点至关重要，因为大多数先前的工作都是在细胞培养模型中进行的，这些模型与人类癌症的相关性有限。最后，我们正在研究细胞周期蛋白 E 周转的机制，因为当该过程失败时，细胞周期蛋白 E 就会解除管制。有趣的是，以细胞周期蛋白 E 为靶点进行泛素介导的蛋白水解的途径也以其他几种癌蛋白为靶点，这强调了其对肿瘤发生的重要性。希望通过了解这些肿瘤发生的基本机制获得的见解将带来癌症预防和治疗的新方法。