RAS SIGNAL TRANSDUCTION IN CELL CYCLE RESPONSE TO RADIATION

放射抵抗是治疗失败的一个主要原因 过度局部性的、可治愈的恶性肿瘤。RAS基因在啮齿动物细胞中的表达 为研究抗辐射方面提供了一个有用的模型系统 表型，因为它允许可靠地产生抗辐射细胞 在相同的遗传背景下。该系统允许实验 确定ras癌基因的信号转导是如何影响的 通过改变转移细胞的细胞周期反应来提高辐射敏感性 以辐射引起的辐射诱导的G2延迟延长。 此应用程序将检查关联的RAS的三个方面 表型。它将研究辐射抗性与G2之间的关系 延迟RAS表达式。我们将阻止RAS操作并确定其影响 关于辐射存活和细胞周期扰动的研究。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，相互作用的信号转导途径的突变成员 用ras和信号转导的抑制剂成分来鉴定 基因表达所必需的关键信号转导元件 RAS相关表型。最后，我们将研究ra表达式是如何 G2过渡的已知效应因子，包括细胞周期蛋白B、cdc2和 Cdc25C。这些研究应该使我们能够开发出一种机械模型 原癌基因的激活表达诱导辐射抗性。在……里面 此外，这些目标的一部分依赖于与其他成员的互动 专门解决杀手/DR5和自动取款机在 抗辐射能力。

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.