MODULATION OF IFN ACTION VIA NOVEL REGULATORY FACTORS

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Interferons (IFN) are a family of multifunctional cytokines that modulate the cellular antitumor, antiviral and immune responses. They are in clinical use for the therapy of human cancers. IFN actions are mediated by IFN stimulated gene (ISG) products. A number of transcription factors are activated though the Janus Kinase-Signal Transducing Activators of Transcription (JAK-STAT) pathway upon stimulation cells with IFNs. Among these is a burgeoning class of transcription factors called the IFN regulatory factors (IRF) which exhibit homology to oncoprotein myb in their DNA binding domains. IRFs are essential for the prevention of leukemia, regulation of apoptosis, cell cycle control and lymphocyte maturation. P48, an IRF family member, is a DNA binding factor which in association with STAT proteins inhibits tumor growth in IFN-treated cells. IFN-gamma enhances biological responses to IFN-alpha/beta through an increase in p48 gene expression in several cells. In cells transformed by dominant viral oncogenes, IFN responses are inhibited because of repression of p48 gene. The gene encoding p48 is modulated in a unique manner by IFN-gamma because it possesses a novel IFN-gamma response element which does not bind known IFN-regulated factors. Based on our preliminary studies we hypothesize that IFN-gamma modulated expression of p48 is mediated novel factors. We now propose to isolate and characterize the genes encoding these factors and determine their role in cell growth inhibition. Preliminary studies indicate that these factors are distinct but are related to families of regulatory factors involved in cell growth function and prevention of tumor growth. It is likely that mutations in these gene products may contribute to resistance to IFN-therapy. Based on such observations we predict that these factors may be essential not only for regulating IFN-action but also for homeostasis of host defenses. We believe that loss of genes encoding these factors may be linked to human cancers. Thus they may serve as markers for monitoring mutations leading to such diseases. These genes may be useful for genetic therapy of cancer, if such mutated genes are discovered. Therefore, it is important to characterize the actions of these novel factors and their role in growth control.