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"Our laboratory is studying 1) signal transduction pathways following exposure of mammalian cells to ionizing radiation and 2) gene therapy in the treatment of neoplastic disease. Recent studies have suggested that radiation exposure is associated with the expression of the c-jun/fos, Egr, and NF-kB gene families. We proposed that the activation of transcription factors is important in transduction of early signals to the expression of late genes which result in the biological response to x-ray-induced damage. Egr-1 and c-jun induction are central to tumor promotion, proliferation, and cycle of radiation and are activated by DNA-damaging agents in mammalian cells. We have defined the DNA elements and mechanisms responsible for radiation activation of Egr-1 and jun. We have extended our work to examine cytoplasmic signaling cascades that induce radiation-induced signals to the nucleus, including MAP kinase, the ribosomal protein S6 kinase pp90rsk, and p56/p53lyn. Gene therapy is generally not well localized. We proposed that ionizing radiation could be used to activate the transcription of exogenous genes that encodes cytotoxic or radioprotective proteins. To test this model, we have generated a vector expressing TNF-alpha under the control of the radiation-responsive Egr-1 promoter. When this construct was used in an experimental animal system, we observed an increase in tumor cures without an increase in normal tissue toxicity. "

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