Endogenous cytokines that belong to the family of Type 1 interferons (including IFNa/p) engage their receptor (1FNAR1/2) to initiate a signaling cascade leading to expression of proteins that play an important role in preventing viral spread and tumor growth. Our preliminary data suggest that in cells that undergo Unfolded Protein Responses (UPR), and perhaps the more broad Integrated Stress Responses (ISR) due to oncogenic activation or oxygen and/ or nutritional deficit, there is an acquired ability to temper responses of these cells to future encounter with IFNa/(3. Based upon our preliminary data and available literature, we propose a hypothesis wherein UPR/ISR inducers suppress Type 1 IFN signaling. This suppression is hypothetically mediated by stimulating the phosphorylation-dependent ubiquitination and downregulation of IFNAR1 and, perhaps, by inactivation of its upstream and/or downstream mediators through expression of UPR-induced miR-211. We also propose that these mechanisms will enable tumor cells to evade the effects of the IFNa/(3 pathway and thereby contribute to the development and progression of tumors. To test our hypothesis, we propose to (i) delineate the mechanisms underlying downregulation of 1FNAR1 and inhibition of cellular responses to IFNa/p by UPR/ISR, and (ii) determine how downregulation of IFNAR1 in the tumor microenvironment affect tumor progression, and (iii) determine the role of these mechanisms in lymphoma development. Completion of this work will provide important knowledge regarding the mechanisms regulating abundance and function of IFN receptors, gain insight for the role of UPR/ISR in the regulation of Type 1 IFN responses, shed the light on the role of these events in tumor development and progression and directly contribute to the identification of novel enzymatic regulators of IFN responses that could be targeted for therapeutic purposes.

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Human cells produce anti-cancer IFNa/p cytokines, yet their effects are evaded by tumors. This application aims to delineate the mechanisms, by which tumor cells harboring specific activated oncogenes and/or starved of oxygen and nutrients are able to escape from IFNa/p control and to determine the role of these mechanisms in development and progression of lymphomas. These proposed studies are important for our understanding of how cancers are formed and potentially may lead to novel therapies.

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