RAS SIGNAL TRANSDUCTION IN CELL CYCLE RESPONSE TO RADIATION

细胞周期辐射反应中的 RAS 信号转导

• 批准号: 6470075
• 负责人: WILLIAM G. MCKENNA
• 金额: $ 14.07万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-06-29 至 2002-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6470075
• 关键词: DNA damage; animal tissue; apoptosis; biological signal transduction; cell cycle; cell cycle proteins; cyclins; enzyme inhibitors; gene expression; gene induction /repression; gene interaction; gene mutation; genetic regulation; human tissue; microinjections; mitogen activated protein kinase; oncogenes; phenotype; phosphoprotein phosphatase; protein kinase; protein structure function; radiation genetics; radiation resistance; radiation sensitivity; synchronous cell division; transfection /expression vector

Radio-resistance is a major cause of treatment failure in patients with overwise localized, curable malignancies. Ras transfection of rodent cells offers a useful model system to study aspects of the radio-resistant phenotype since it allows the reliable creation of radio-resistant cells on a uniform genetic background. This system permits experiments to determine how signal transduction through the ras oncogene is affecting radio-sensitivity by altering the cell cycle response of transferred cells to radiation causing a prolongation of the radiation induced G2 delay. This application will examine three aspects of the ras associated phenotype. It will examine the relationship of radio-resistance and the G2 delay to ras expression. We will block ras action and determine the effect on radiation survival and cell cycle perturbations. It will begin to dissect which of the ras signal transduction pathways is involved in the induction of radio-resistance. We will utilize ras effector domain mutants, mutant members of signal transduction pathways which interact with ras and inhibitors of signal transduction components to identify the key signal transduction elements which are necessary for expression of the ras associated phenotypes. Finally, we will examine how ra expression effects known effectors of the G2 transition, including cyclin B, cdc2 and cdc25C. These studies should enable us to develop a mechanistic model for the induction of radiation resistance by activated oncogene expression. In addition, portions of these aims rely on interactions with other members of the group to specifically address the role of KILLER/DR5 and ATM in radio-resistance.

放射抵抗是导致治疗失败的主要原因 过于局部，可治愈的恶性肿瘤。啮齿动物细胞的RAS转染 提供了一个有用的模型系统来研究耐电的方面 表型，因为它允许可靠的放射电池创建 在统一的遗传背景上。该系统允许实验 确定信号通过RAS癌基因如何影响信号 通过改变转移细胞的细胞周期响应的无线电敏感性 辐射导致辐射延长引起的G2延迟。 该应用程序将检查与RAS相关的三个方面 表型。它将检查放射抵抗与G2的关系 延迟到RAS表达。我们将阻止RAS动作并确定效果 关于辐射存活和细胞周期扰动。它将开始 剖析涉及哪种RAS信号转导途径 抗抗性。我们将利用RAS效应域 突变体，相互作用的信号转导途径的突变体 与RAS和信号转导组件的抑制剂一起识别 表达所必需的关键信号转导元素 RAS相关表型。最后，我们将研究RA表达方式 效果G2转变的已知效应子，包括细胞周期蛋白B，CDC2和 cdc25c。这些研究应该使我们能够为 通过激活的癌基因表达诱导辐射抗性。在 此外，这些目标的一部分依赖于与其他成员的互动 该小组专门解决杀手级/DR5和ATM在 抗性。