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: 7246603
• 负责人: Steven I Reed
• 金额: $ 33.46万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-08-01 至 2008-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7246603
• 关键词: Ablation; Address; Affect; Anabolism; Anaphase; Appearance; Cell Cycle; Cell Cycle Proteins; Cultured Cells; Cyclin E; DNA biosynthesis; Data; F-Box Proteins; FBXW7 gene; G1 Phase; Genes; Genomic Instability; Growth; Human; Investigation; Lead; Link; Loss of Heterozygosity; Malignant Neoplasms; Mammals; Mammary Neoplasms; Mammary gland; Mediating; Metaphase; Mitosis; Mitotic; Modeling; Mus; Mutation; Numbers; Ovary; Patients; Phase; Phase Transition; Phosphorylation; Phosphorylation Site; Polyploidy; Pre-Replication Complex; Process; Protein Isoforms; Proteolysis; RNA Splicing; Regulation; Role; Sampling; Site; Specificity; Testis; Time; Tissues; Transgenes; Transgenic Organisms; Tumor Suppressor Proteins; Ubiquitin-Protein Ligase Complexes; Ubiquitination; Variant; carcinogenesis; cell type; chromosome loss; design; improved; insight; mammary epithelium; mouse model; outcome forecast; tumorigenesis; ubiquitin-protein ligase

DESCRIPTION (provided by applicant): Cyclin E is a critical cell cycle regulatory protein. At the same time, deregulation of cyclin E expression has been linked to carcinogenesis both in human patients and in mouse models. The current proposal constitutes an ongoing project aimed at gaining understanding into how cyclin E is normally regulated and to elucidate the mechanisms whereby cyclin E expression becomes deregulated and promotes carcinogenesis, respectively. The proposal is divided into three specific aims, the first of which addresses the mechanism of cyclin E degradation in cultured cells and in mice. The role of specific phosphorylation sites on cyclin E will be explored as well as the contribution of a new SCF protein ubiquitin ligase defined by the F-box protein hCdc4. The second specific aim is targeted at the mechanism whereby deregulation of cyclin E confers genomic instability, likely to be a contributing factor in cyclin E-mediated carcinogenesis. Two hypotheses will be explored in detail: that deregulation of cyclin E impairs DNA replication by interfering with pre-replication complex assembly and that elevated cyclin E levels in mitosis block the metaphase-anaphase transition by inhibiting the essential mitotic protein ubiquitin ligase known as APC. The final specific aim seeks to gain a better understanding of the link between cyclin E deregulation and carcinogenesis. Mouse models will be employed to determine if cyclin E promotes carcinogenesis by accelerating loss of heterozygosity (LOH) at tumor suppressor loci. It is hoped that these investigations will provide insights that will ultimately lead to improved prognosis and therapy.

描述（由申请人提供）：细胞周期蛋白E是关键细胞周期调节蛋白。同时，在人类患者和小鼠模型中，细胞周期蛋白E表达的失调与癌变有关。当前的提案构成了一个旨在了解cyclin e通常调节的项目，并阐明了细胞周期蛋白E表达的机制，分别对细胞周期蛋白表达进行了调节并促进致癌作用。该提案分为三个特定的目标，第一个目的是解决培养细胞和小鼠中细胞周期降解的机理。将探索特定磷酸化位点在细胞周期蛋白E中的作用，以及由F-box蛋白HCDC4定义的新SCF蛋白泛素连接酶的贡献。第二个特定目的是针对细胞周期蛋白E赋予基因组不稳定性的机制，这可能是细胞周期蛋白电子介导的癌变的一个因素。将详细探讨两个假设：细胞周期蛋白E通过干扰预复合复合物组装而损害DNA复制，并通过抑制所谓有丝分裂蛋白的泛素泛素ligase（已知APC）来阻止中期 - 移动酶过渡中的细胞周期蛋白E水平升高。最终的特定目的旨在更好地了解细胞周期蛋白消耗管制与癌变之间的联系。将采用小鼠模型来确定细胞周期蛋白是否通过加速肿瘤抑制基因座的杂合性（LOH）损失来促进癌变。希望这些调查能够提供见解，最终会改善预后和治疗。