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，在细胞周期中进行 确保细胞分裂伴随生长。相比之下，终端 分化之前通常会出现细胞周期停滞和 停止扩散。是扩散还是保留的决定 静止期最常发生在细胞周期的G1期。 体细胞必须正确地处理这一决定，才能适当地 保持动态平衡。这样的管理需要对细胞进行调节 控制G1-S过渡的循环机械。这包括基因 扩增阳性细胞周期效应因子，如细胞周期蛋白D1，以及 肿瘤抑制基因pRb、p16等负性效应基因突变。 这些分子是控制细胞的分子途径的一部分。 对正性和负性细胞外效应物的周期反应 细胞生长。调控这些分子的一个主要目标是 ES2F/DP异源二聚体转录因子家族。E2F/DP/1/S控制 基因的表达是生长和DNA复制所必需的。近期 结果表明，E2F/DP功能的扰动在体外和 体内也可以致癌。 E2F/DP及其已知的上游调控因子在果蝇中都是保守的 在那里我们可以将复杂的遗传方法应用于 E2F/DP功能分析。在果蝇中，dE2F/DDP是必需的 正常发育。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程。这个 这项提议的目标是1)从基因上识别新的果蝇 调节dE2F/DDP活性的基因，因此可能调节 细胞周期的G1-S转变；2)了解dE2F/DDP是如何 体内转录调控及其对细胞周期控制的影响 在开发过程中。