MOLECULAR STUDIES OF RADIATION RESISTANT TUMOR CELLS

信号转导通路在细胞反应中发挥重要作用 电离辐射。我们最近观察到其中一条路径， 涉及转录因子NF-khib/ikhib的信号转导与T 人类遗传病患者细胞的极端辐射敏感性 疾病，共济失调毛细血管扩张(AT)。此外，还进行了初步试验。 人鳞状细胞癌细胞(SCCs)显示，核因子的成分- Khib/-Ikhib复合体在不同水平上表达，并显示出 邮件大小的差异。因为这些细胞系以前 表现出不同的本征辐射敏感性，我们建议 探讨核因子-核因子-khib/核因子-khib在辐射敏感人群中的作用 和抗辐射的人类肿瘤细胞(SCCs)。我们将测试 假设核因子-khib调节受损会导致更多的辐射 敏感的细胞表型。 使用三辐射敏感和三辐射的模型细胞系统 耐药鳞状细胞，我们将测量表达水平和结构完整性 编码核因子-khibeta/1khibeta复合体组件的基因。DNA- 蛋白质结合分析和报告基因表达分析将确定 复合体各组成部分的功能完整性。化学药品和 生物抑制实验将确定是否具有辐射抗性 通过以下方法可以使细胞对电离辐射的反应更加敏感 干扰核因子-khibeta信号通路。 这项建议中的实验的完成将为我们提供 核因子-khibeta途径及其与细胞辐射反应的关系。 这样的知识可以识别有用的分子信息 提高癌症治疗水平的诊断和治疗策略 治疗比率。

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.