Interferons (IFNs) are a family of multifunctional cytokines occurring in vertebrates. They have antiviral antiprotozoal, cell growth regulatory, and immunomodulatory activities. These are three kinds of IFNs: alpha, beta gamma. The alpha and beta IFNs share similar sequences. Their information can be induced in a large variety of cells by viruses, double-stranded RNA, and mitogens. The formation of gamma IFN can be induced in lymphocytes by antigens to which the cells had been sensitized and by mitogens. The IFNs produced are secreted. They interact with specific cell surface receptors on cells and alter the biological and biochemical characteristics of the cells. At least some of the alterations are mediated by proteins whose formation is induced by the IFNs. The induced proteins include enzymes, e.g., at least four (2'-5') oligoadenylate synthetase isoenzymes and eIF-2 kinase. The listed enzymes are latent unless activated by binding double-stranded RNA. They were shown to be among the mediators of the antiviral activities of IFNs. We have isolated several cDNA clones which correspond to MRNAs whose levels are increased in cells exposed to IFNs. We have also identified genes whose rate of transcription is increased by IFNs. The upstream flanking regions of these genes include sequences which are IFN-activatable enhancers. We characterized a cluster of at least six adjacent, IFN-activatable genes which is closely linked to the erythroid alpha spectrin, the serum amyloid protein, and the mixed lymphocyte-stimulatory loci on murine chromosome 1. Partial sequencing of these genes and complete sequencing of two cDNAs revealed that there is much sequence similarity between the genes in the cluster and also between the 5' flanking regions of at least three of the genes, and that the cluster arose in consequence of repeated gene multiplications. The expression of the genes in the cluster is apparently coordinately regulated by IFNs. We are planning to continue with the characterization of the cluster by (a) completing the sequencing of the cCDNAs corresponding to its genes, (b) preparing antibodies to the proteins specified and using these to determine the tissue distribution and subcellular localization of the proteins, (c) completing the cosmid mapping of the region and searching for further, adjacent, IFN- activatable genes, and (d) studying the functions of the proteins specified by transfecting into mammalian cells constitutive expression vectors and examining the growth characteristics, the antiviral state, and the immunological characteristics of the transfected cells. Other projects in the laboratory concern (a) the identification of the RNA activating the latent, IFN- inducible, (2'-5') oligoadenylate synthetase isoenzymes in various virus-infected cells and uninfected cells; (b) the determination if the inhibition of the early phase of SV40 infection by IFNs is mediated by double stranded RNA-dependent pathways, and (c) the possible role of translational control in the inhibition of cell proliferation by IFNs.
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