MOLECULAR STUDIES OF RADIATION RESISTANT TUMOR CELLS

信号转导通路在细胞对 电离辐射我们最近观察到，其中一条途径， 涉及转录因子NF-κ B/ikhib的转录因子，与肿瘤的发生有关。 人类遗传病患者的细胞对辐射的极端敏感性 共济失调毛细血管扩张症（AT）。此外，初步实验， 人鳞状细胞癌细胞（SCC）显示NF-κ B组分， khib/-Ikhib复合物在不同水平表达，并显示出 消息大小的差异。由于这些细胞系之前已经被 其特征在于显示各种固有的辐射敏感性，我们建议 研究NF-NF-khib/NF-khib在这些辐射敏感细胞中的功能， 和抗辐射的人肿瘤细胞（SCC）。我们将测试 假设受损的NF-κ B调节导致更多的辐射 敏感的细胞表型。 利用三辐射敏感和三辐射敏感的模型细胞系统， 我们将检测耐药SCC的表达水平和结构完整性， 编码NF-κ B/1 κ B复合物成分的基因。DNA- 蛋白结合试验和报告基因表达试验将确定 复合体各组成部分的功能完整性。化学和 生物抑制实验将确定是否具有辐射抗性， 细胞对电离辐射的反应可以通过 干扰NF-κ B信号通路。 本提案中实验的完成将为我们提供深入的了解， NF-κ B通路及其与细胞辐射反应关系。 这样的知识可以识别有用的分子信息，以应用于 改善癌症治疗的诊断和治疗策略 治疗比

Signal transduction pathways play important roles in cellular responses to ionizing radiation. We have recently observed that one of these pathways, that involving the transcriptional factor NF-khib/ikhib, is implicated in t extreme radiation sensitivity of cells from patients with the human genetic disease, ataxia telangiectasia (AT). Furthermore, prelimary experiments wit human squamous carcinoma cells (SCCs) reveal that components of the NF- khib/-Ikhib complex are expressed at various levels, and show evidence of differences in message size. Since these cell lines have been previously characterized to show various intrinsic radiation sensitivities, we propose to investigate NF-NF-khib/NF-khib function in these radiation sensitive and radiation resistant human tumor cells (SCCs). We will test the hypothesis that impaired NF-khib regulation results in a more radiation sensitive cellular phenotype. Using a model cell system of three radiation sensitive and three radiation resistant SCCs, we will measure expression levels and structural integritie of genes coding for components of the NF-khibeta/1khibeta complex. DNA- protein binding assays, and reporter gene expression assays will determine the functional integrity of components of the complex. Chemical and biological inhibition experiments will determine whether radiation resistan cells can be made more sensitive in their response to ionizing radiation by interfering with the NF-khibeta signaling pathways. The completion of the experiments in this proposal will provide insight int the NF-khibeta pathway and its relationship to cellular radiation response. Such knowledge may identify useful molecular information for application in diagnostic and therapeutic strategies to improve the cancer treatment therapeutic ratio.