Interferons (IFNs) are small polypeptides that not only cause cells to become resistant to viral infection but are among the most powerful natural growth regulatory substances that we know. They act by binding to specific cell surface receptors. The first effects of ligand- receptor interaction are changes in the rate of transcription of a limited set of genes in the nucleus of the cell. The major aims of this research are to understand the mechanisms by which these changes in gene transcription are brought about after IFN attachment to cells.
The specific aims are to purify the proteins and then clone the genes encoding the proteins which we can demonstrate bind to DNA sequences required for IFN induction of transcription. In the case of IFN-alpha gene stimulation we have identified a factor, ISGF-3, composed of four proteins that reside in the cytoplasm of the untreated cell awaiting activation to become a positive acting nuclear transcription factor. The amino acid sequence of each of four proteins that make up ISGF-3 is being obtained now and the genes for all four proteins (113, 91, 84 and 48KD) must be obtained, sequenced and used in recombinant DNA form to map functional domains and to produce antibodies to study protein association. In the case of IFN-gamma stimulation of gene transcription a new immediately responsive, IFN-gamma dependent positive acting factor, GAF (gamma activity factor), and its IFN-gamma responsive DNA element have been defined. This will allow the purification of GAF and the cloning of genes encoding its proteins. In this way we can compare proteins whose transcriptional stimulation depends on activation by two different specific ligands acting on two different receptors, the overall outcome of which is to induce the antiviral state or slow cell growth. The health relatedness of understanding details of action of these two cytokines are quite direct: not only do both IFN-alpha and -gamma cause growth inhibition in many different cell types in culture, there is often a potentiation with both ligands. Knowing which intracellular molecules are primarily affected by each and by both ligands may help target IFN therapy more precisely both in establishing growth restraint and in inducing the anti-viral state.
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