Role of the UPR in myc-induced tumorigenesis

UPR 在 myc 诱导的肿瘤发生中的作用

• 批准号: 9329280
• 负责人: Constantinos Koumenis
• 金额: $ 26.1万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9329280
• 关键词: ATF6 gene; Ablation; Acute; Alpha Cell; Animal Model; Animals; Anoxia; Antioxidants; Apoptosis; Apoptotic; Autophagocytosis; B-Lymphocytes; Cell Death; Cell Line; Cell Survival; Cells; Cellular Stress Response; Chromosomal translocation; Client; Clinical; Colorectal Cancer; Cytoprotection; Deletion Mutation; Development; Endoplasmic Reticulum; Enhancers; Equilibrium; Gene Amplification; Gene Expression; Genetic; Genetic Models; Genetic Transcription; Homeostasis; Human; Hypoxia; In Vitro; Instruction; Interferon-alpha; Interferons; Lead; Link; Lymphocyte; Lymphoma; Lymphomagenesis; Malignant Neoplasms; Metabolic stress; MicroRNAs; Modeling; Molecular Chaperones; Mus; Neuroblastoma; Normal tissue morphology; Nude Mice; Oncogenes; Oncogenic; PERK kinase; Pathway interactions; Patients; Pharmacology; Phosphorylation; Phosphotransferases; Play; Protein Biosynthesis; Proteins; Proteolytic Processing; Reactive Oxygen Species; Recovery; Regulation; Resistance; Ribosomal Proteins; Role; Sampling; Small Interfering RNA; Stress; Testing; Time; Transgenic Mice; Tumorigenicity; Up-Regulation; antitumor agent; arm; c-myc Genes; c-myc Proto-Oncogenes; cell transformation; cohort; design; endoplasmic reticulum stress; experience; experimental study; in vivo; inhibition of autophagy; inhibitor/antagonist; killings; misfolded protein; mouse model; neoplastic cell; new therapeutic target; novel; nutrient deprivation; overexpression; programs; promoter; proteostasis; response; response biomarker; restoration; senescence; small hairpin RNA; transcription factor; translation factor; tumor; tumor growth; tumor microenvironment; tumorigenesis; tumorigenic

The Unfolded Protein Response (UPR) is a cellular homeostatic program initiated by an excess of unfolded/misfolded client proteins in the Endoplasmic Reticulum (ER) lumen, with primarily a cytoprotective effect. We previously showed that tumor cell survival under hypoxic and nutrient deprivation stress is dependent on the ER resident protein and UPR effector PERK. In addition to the tumor microenvironment, oncogenes are also known to activate cellular stress responses, including metabolic stress, apoptosis, and senescence. MYC is the target of chromosomal translocation or gene amplification during the development of many human cancers. c-Myc expression has been associated with robust upregulation of both total cellular protein content and rates of protein synthesis. This finding raises the possibility that c-Myc-transformed cells experience a higher than normal level of ER stress. In preliminary studies, we have used multiple genetic models of regulated c-Myc activation, to demonstrate that Myc activates the PERK/elF2α/Atf4 arm of the UPR. Activation of the UPR leads to increased cell survival via the induction of cytoprotective autophagy and reduced release of Ca^* from the ER. PERK ablation significantly reduced Myc-induced autophagy, cell transformation and tumor formation in nude mice. Samples from Eμ-Myc mice and human lymphomas demonstrate higher levels of UPR activation, compared to corresponding normal tissues. We hypothesize that the increase in protein burden in cells overexpressing c-Myc results in ER stress and activation of the UPR which tempers ER stress and facilitates transformation and tumor growth. This hypothesis will be tested in four specific aims: In Aim 1, we will determine the requirement for elF2α phosphorylation, ATF4 and Chop induction, Nrf2 activation and miRNA 211 in c-Myc-induced transformation in vitro and in vivo. In specific Aim 2, we will elucidate the mechanism of cytoprotection afforded by UPR activation in the context of oncogenic transformation by Myc. Under specific Aim 3, we will investigate the impact of c-Myc overexpression on the activation of the other two major UPR pathways. In specific Aim 4, we will determine the role of PERK activation in c-Myc induced lymphomagenesis using a transgenic mouse model. Successful completion of these studies would establish, for the first time, Myc upregulation as a cell-autonomous activator of UPR and would unveil novel targets for inhibiting Myc-dependent tumorigenesis.

展开的蛋白质反应（UPR）是一个细胞稳态程序，该程序由过量 内质网中（ER）中展开/错误折叠的客户蛋白，主要A 细胞保护作用。我们先前表明肿瘤细胞在低氧和营养剥夺下的存活率 应力取决于ER居民蛋白质和UPR效应子PERK。除了肿瘤 微环境，癌基因也已知会激活细胞应激反应，包括代谢 压力，凋亡和感应。 MYC是染色体易位或基因扩增的目标 在许多人类癌症的发展过程中。 C-MYC表达与鲁棒 总细胞蛋白含量和蛋白质合成速率的上调。这一发现提高了 C-MYC转化的细胞的可能性高于正常水平的ER应激水平。在初步 研究，我们使用了多种调节C-MYC激活的遗传模型，以证明MYC 激活UPR的PERK/ELF2α/ATF4臂。 UPR的激活导致通过 诱导细胞保护自噬并减少Ca^*从ER释放。振兴消融 裸鼠的自噬，细胞转化和肿瘤形成大大降低了。 来自Eμ-Myc小鼠和人淋巴瘤的样品表现出更高水平的UPR激活， 与相应的正常组织相比。我们假设细胞中蛋白质燃烧的增加 过表达的C-MYC导致ER应力和UPR激活，从而导致ER应力和 促进转化和肿瘤生长。该假设将以四个具体目的进行检验：在AIM 1中， 我们将确定对ELF2α磷酸化，ATF4和CHOP诱导，NRF2激活的要求 在C-MYC诱导的体外和体内转化中的miRNA 211。在特定目标2中，我们将阐明 UPR激活提供的细胞保护机制在致癌的背景下通过 妈妈。在特定目标3下，我们将研究C-MYC过表达对激活的影响 其他两个主要的UPR途径。在特定目标4中，我们将确定PERK激活在C-MYC中的作用 使用转基因小鼠模型诱导的淋巴细胞化。这些研究成功完成 将首次确定MYC上调为UPR的细胞自主激活剂，并且将 揭示了抑制MYC依赖性肿瘤发生的新型靶标。