UPR, interferon signaling and tumorigenesis

属于1型干扰素家族的内源性细胞因子(包括IFNA/p)参与其 受体(1FNAR1/2)启动信号级联反应，导致蛋白表达发挥重要作用 在防止病毒传播和肿瘤生长方面的作用。我们的初步数据表明，在经历了 未折叠蛋白反应(UPR)，可能还有更广泛的综合应激反应(ISR)，原因是 致癌活性或缺氧和/或营养缺乏，有一种后天的能力来缓和反应 根据我们的初步数据和现有文献，我们 提出一种假设，其中UPR/ISR诱导剂抑制1型干扰素信号。这种压制是 假说通过刺激依赖于磷酸化的泛素化和下调 IFNAR1，并可能通过以下方式使其上游和/或下游介体失活 UPR诱导的miR-211。我们还提出，这些机制将使肿瘤细胞能够逃避这种影响 IFNA/(3)途径的表达，从而促进肿瘤的发生和发展。测试我们的 假设，我们建议(I)描述1FNAR1下调和抑制的潜在机制 UPR/ISR对IFNA/p的细胞反应，以及(Ii)确定肿瘤中IFNAR1的下调 微环境影响肿瘤进展，以及(Iii)确定这些机制在淋巴瘤中的作用 发展。 这项工作的完成将提供关于调节机制的重要知识 干扰素受体的丰度和功能，了解UPR/ISR在1型干扰素调控中的作用 反应，阐明了这些事件在肿瘤发生和发展中的作用，并直接 有助于识别可作为靶向的干扰素反应的新的酶调节因子 治疗目的。

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.