GENETIC ANALYSIS OF E2F FUNCTION DURING DEVELOPMENT

发育过程中 E2F 功能的遗传分析

• 批准号: 6138663
• 负责人: Robert J Duronio
• 金额: $ 22.96万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-01-01 至 2003-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6138663
• 关键词: Drosophilidae; cell growth regulation; cytogenetics; developmental genetics; embryogenesis; gene expression; gene induction /repression; gene mutation; genetic regulatory element; genetic transcription; molecular cloning; nucleic acid sequence; oligonucleotides; phenotype; protein structure function; synchronous cell division; transcription factor

Controlling the cell division cycle is an essential part of normal animal development. In proliferating tissues, progression through the cell cycle assures that cell division accompanies growth. In contrast, terminal differentiation is typically preceded by cell cycle arrest and the cessation of proliferation. The decision to proliferate or remain quiescent is most often made during the G1 phase of the cell cycle. Somatic cells must correctly manage this decision in order to properly maintain homeostasis. Such management requires regulation of the cell cycle machinery controlling the G1-S transition. This includes gene amplification of positive cell cycle effectors such as cyclin D1, and mutation of negative effectors such as tumor suppressors pRB and p16. These molecules are part of a molecular pathway that controls the cell cycle in response to both positive and negative extracellular effectors of cell growth. A major target of regulation of these molecules is the ES2F/DP family of heterodimeric transcription factors. E2F/DP/1/s control the expression of genes require for growth and DNA replication. Recent results indicate that perturbations of E2F/DP function both in vitro and in vivo can also be oncogenic. E2F/DP and its known upstream regulators are all conserved in Drosophila melanogaster, where we can apply sophisticated genetic approaches to an analysis of E2F/DP function. In Drosophila, dE2F/dDP is required for normal development. Thus, developmental signals that control cell fate may regulate growth and cell cycle progress via altering E2F/DP activity. The goals of this proposal are 1) to genetically identify novel Drosophila genes that regulate the activity of dE2F/dDP and therefore may regulate the G1-S transitions of the cell-cycle, and 2) to understand how dE2F/dDP regulates transcription in vivo and how this affects cell cycle control during development.

控制细胞分裂周期是正常动物的重要组成部分 发展。在增殖组织中，通过细胞周期发展 确保细胞分裂伴随生长。相反，终端 分化通常在细胞周期停滞之前 停止增殖。决定扩散或留下的决定 静态通常是在细胞周期的G1阶段进行的。 体细胞必须正确管理此决定才能正确 保持体内平衡。这样的管理需要调节细胞 控制G1-S过渡的循环机械。这包括基因 阳性细胞周期效应子（例如细胞周期蛋白D1）的扩增和 负面效应子（如肿瘤抑制器PRB和P16）的突变。 这些分子是控制细胞的分子途径的一部分 响应于正面和负面细胞外效应子的循环 细胞生长。 这些分子调节的主要目标是 异二聚体转录因子的ES2F/DP家族。 E2F/DP/1/S控件 基因的表达需要生长和DNA复制。最近的 结果表明，E2F/DP的扰动在体外和 体内也可能是致癌的。 E2F/DP及其已知的上游调节器均在果蝇中保守 Melanogaster，我们可以在其中应用复杂的遗传方法 E2F/DP功能的分析。在果蝇中，需要DE2F/DDP 正常发展。因此，控制细胞命运的发育信号可能 通过改变E2F/DP活性来调节生长和细胞周期进展。这 该提议的目标是1）遗传识别新型果蝇 调节DE2F/DDP活性的基因可能会调节 细胞周期的G1-S转变，以及2）了解DE2F/DDP的方式 调节体内转录，这如何影响细胞周期控制 在开发过程中。