Tumor Necrosis Factor (TNF) was first discovered by its ability to kill certain tumors in mice. Since then, a wide variety of cellular responses to TNF have been described. Among them is the ability of TNF to induce protection or resistance to its own cytotoxic actions. This protection has been shown to require the synthesis of TNF-induced mRNA and protein. The genes and the protein products that give rise to this resistance have yet to be characterized. The goals of this proposal are to clone and characterize the genes that are induced by TNF in transformed mouse fibroblasts. Experiments will be carried out to examine the regulation and expression of these genes in closely related transformed fibroblasts that are both sensitive and resistant to TNF cytotoxicity. The expression of these genes in other cell types will also be examined. The cloned cDNAs will be assayed for their ability to protect sensitive cells form TNF- mediated transfection assay. In addition, the regulation of these genes in transplanted tumors will be studied in vivo. The results of these experiments will: provide a broad outline of the TNF-mediated gene expression; correlate gene expression with resistance to TNF; and provide reagents that can be used to uncover the mechanisms of TNF actions. Identification of genes that are involved in or directly cause resistance to the cytotoxic effects of TNF is potentially useful in therapeutic strategies of tumor treatment.
