Cytokine Signaling

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DESCRIPTION (provided by applicant): Type I Interferons (IFNs) are the first line of defense against viral infections and play an important role in the regulation of cell proliferation. Both effects require the activation of the Jak-STAT pathway however, IFNs activate other pathways that also intervene in its antiviral and antiproliferative functions. The mechanism of the growth inhibitory action of type I IFNs is not completely clear. Moreover, depending on the context, IFNs can have either a cytostatic effect, induce apoptosis, or cells can be completely resistant. In order to discover new proteins that may intervene in the biological effects of type I IFNs, we performed a two-hybrid screening using the IFN-R chains as bait. We have cloned a gene termed BARA. BARA interacts with the betaL chain of the type I interferon receptor. The homolog of BARA in C. elegans is part of the Cyclin D-CDK4-retinoblastoma (RB) pathway (termed pathway B), which in conjunction with another redundant pathway (termed pathway A) negatively regulate cell cycle progression and vulval development. This project will focus on the role of BARA on the cell growth inhibitory effects of type I IFNs. In Specific Aim 1 we will determine the role of BARA in IFN-induced growth inhibitory effect, apoptosis and cell senescence. In Specific Aim 2 we will test the hypothesis that the IFN system is the mammalian equivalent to a pathway (pathways B) that in C. elegans negatively regulates EGF-RAS-MAPK pathway. In Specific Aims 3 we will determine if mice with a homozygous deletion of the BARA gene have alterations of the IFN system. We expect that the goals to be achieved with this proposal will shed light on the understanding of the growth regulatory effects of type I IFNs.