RAS SIGNAL TRANSDUCTION IN CELL CYCLE RESPONSE TO RADIATION

放射性抵抗是治疗失败的主要原因， 过度局限的可治愈的恶性肿瘤Ras转染啮齿动物细胞 提供了一个有用的模型系统来研究抗辐射的各个方面， 表型，因为它允许可靠地产生抗辐射细胞 有着相同的遗传背景该系统允许实验 确定通过ras癌基因的信号转导如何影响 通过改变转移细胞的细胞周期反应的放射敏感性 辐射导致辐射诱导的G2延迟的延长。 本应用程序将研究相关RAS的三个方面 表型本研究将探讨辐射抗性与G2 ras表达延迟。我们将阻止ras行动并确定效果 辐射存活和细胞周期紊乱的影响。它将开始 剖析哪些ras信号转导通路参与了 辐射抗性的诱导。我们将利用ras效应域 突变体，信号转导通路的突变成员， 与ras和信号转导抑制剂成分，以确定 关键的信号转导元件是表达所必需的 ras相关表型。最后，我们将研究ra表达式 影响已知的G2转换效应物，包括细胞周期蛋白B，cdc 2和 cdc25C。这些研究应该使我们能够开发一个机械模型， 通过激活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 专门讨论KILLER/DR 5和ATM在 抗辐射性

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.