EGF SIGNAL TRANSDUCTION AND RADIATION RESPONSE

相当数量的人类恶性肿瘤含有高水平的 生长因子受体。表皮生长因子受体(EGF-R) 据报道，有几个人的基因过度表达或表达改变 肿瘤，尤其是鳞癌。我们发现，表皮 生长因子(EGF)是鳞癌(SC)的辐射增敏剂 过度表达EGF-R的细胞我们假设EGF暴露于 防止过度表达EGF-R的受照射细胞建立 调节或竞争对辐射损伤的有效反应 用于常见的信号通路。 我们将研究重要的生化过程或分子事件 参与EGF信号转导和信号的汇聚 与辐射损伤有关。我们建议确定以下组件 EGF诱导放射增敏的事件研究与比较 两种SC细胞系：A431，EGF辐射增敏；SIHA，SIHA 不受EGF的辐射增敏。A431细胞(A431-R)将包括在 允许EGF诱导的放射增敏与生长效应分离 EGF的基因。未经辐射的A431和SiHA细胞的初步结果显示 表面EGF-R密度和程度的显著差异 蛋白质酪氨酸磷酸化动力学。我们发现在经过辐射的 A431细胞认为EGF信号转导途径与 经典辐射诱导的G2期停滞以及辐射对 EGF诱导的G1期停滞。我们将扩展这些初步研究，并 比较酪氨酸和丝氨酸/苏氨酸的变化幅度和动力学 磷酸化级联，特定的丝裂原反应活性 激酶与特定细胞周期调控活性的变化 EGF诱导的非同步辐射增敏分析中的蛋白质 以及同步的A431、A431-R和SIHA培养。侯选人 放射增敏事件将是那些显著不同的事件 在数量上或质量上在细胞系中。 这些研究将提供对发出信号的基本机制的洞察 引起生化变化和基因表达的变化以响应 放射线和表皮生长因子。最终，这些信息可能会被用于设计 利用特定信号转导的放射增敏策略 肿瘤细胞中的通路。

A significant number of malignant human tumors contain high levels of growth factor receptors. Epidermal growth factor receptor (EGF-R) overexpression or altered expression has been reported for several human tumors, particularly squamous carcinomas. We discovered that epidermal growth factor (EGF) is a radiation sensitizer of squamous carcinoma (SC) cells that overexpress the EGF-R. We hypothesize that EGF exposure prevents irradiated cells that overexpress the EGF-R from establishing an effective response to radiation-induced damage by modulating or competing for common signaling pathways. We will investigate important biochemical processes or molecular events involved in the convergence of EGF signal transduction and signals associated with radiation damage. We propose to identify components of EGF-induced radiosensitization by investigating and comparing events in two SC cell lines: A431, which is radiosensitized by EGF, and SiHa, which is not radiosensitized by EGF. A431 cells (A43l-R) will be included that allow EGF-induced radiosensitization to be separated from growth effects of EGF. Preliminary results in nonirradiated A431 and SiHa cells show significant differences in surface EGF-R density and the extent and kinetics of protein tyrosine phosphorylation. We have found in irradiated A431 cells that EGF signal transduction has points of convergence with the classical radiation-induced G2 arrest and with the effect of radiation on an EGF-induced G1 arrest. We will extend these preliminary studies and compare the extent and kinetics of tyrosine and serine/threonine phosphorylation cascades, the activities of specific mitogen-responsive kinases, and changes in the activities of specific cell-cycle control proteins in an analysis of EGF-induced radiosensitization in asynchronous and synchronous A431, A431-R, and SiHa cultures. Candidate radiosensitizing events will be those that differ significantly either quantitatively or qualitatively among the cell lines. These studies will provide insight into basic mechanisms of signaling that cause biochemical changes and changes in gene expression in response to radiation and EGF. Ultimately, this information may be used in the design of radiosensitizing strategies that exploit specific signal transduction pathways in tumor cells.