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.
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