UPR, interferon signaling and tumorigenesis

UPR、干扰素信号传导和肿瘤发生

基本信息

批准号：
8596374
负责人：
Serge Y Fuchs
金额：
$ 30.96万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-18 至 2018-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8596374
关键词：
Affect Benign Cell Death Cell Proliferation Cells Data Development Down-Regulation Endocytosis Event Exposure to Family Future Homeostasis Human IFNAR1 gene IFNAR2 gene Instruction Interferon-alpha Interferons Knowledge Lead Ligands Light Literature Lymphoma Lysosomes MAPK14 gene Malignant Neoplasms Mediating Mediator of activation protein Nutrient Nutritional Oncogenes Oncogenic Oxygen Pathogenesis Pathway interactions Phosphorylation Phosphotransferases Play Production Protein Biosynthesis Proteins Regulation Role Signal Transduction Stimulus Stress Testing Tissues Tumor Immunity Ubiquitination Vascular Endothelial Growth Factors Viral Work angiogenesis autocrine base biological adaptation to stress c-myc Genes casein kinase cell type cytokine insight neoplastic cell novel paracrine prevent protein expression receptor response therapeutic target tumor tumor growth tumor microenvironment tumor progression tumorigenesis tumorigenic

项目摘要

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.

属于1型干扰素家族的内源性细胞因子（包括IFNA/P）受体（1FNAR1/2）启动信号级联反应，导致表达蛋白质的表达在预防病毒扩散和肿瘤生长中的作用。我们的初步数据表明，在经历的细胞中展开的蛋白质反应（UPR），以及由于致癌激活或氧气和/或营养缺陷，有能力降低反应的能力这些单元将未来与IFNA的接触/（3。基于我们的初步数据和可用文献，我们提出一个假设，其中UPR/ISR诱导剂抑制1型IFN信号传导。这种抑制是假设通过刺激磷酸化依赖性的泛素化和下调 IFNAR1，也许是通过表达其上游和/或下游介体的灭活 UPR诱导的miR-211。我们还建议这些机制将使肿瘤细胞能够逃避影响 IFNA/（3途径，从而有助于肿瘤的发展和进展。假设，我们建议（i）描述1FNAR1下调和抑制的机制通过UPR/ISR对IFNA/P的细胞反应，（ii）确定肿瘤中IFNAR1的下调微环境影响肿瘤进展，（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有关调节机制的重要知识 IFN受体的丰度和功能，可以洞悉UPR/ISR在1型IFN中的作用反应，阐明了这些事件在肿瘤发育和进展中的作用以及直接有助于鉴定可以针对的IFN反应的新型酶调节剂治疗目的。