The Role of ATF4 in Promoting c-Myc Induced Lymphomagenesis

ATF4 在促进 c-Myc 诱导的淋巴瘤发生中的作用

基本信息

批准号：
8792817
负责人：
Feven Tameire
金额：
$ 4.31万
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：
2013-12-13 至 2015-12-12
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8792817
关键词：
Ablation Allografting Amino Acids Analysis of Variance Antioxidants Apoptosis Attenuated Autophagocytosis B-Cell Lymphomas B-Lymphocytes Biological Assay Biological Models Biological Process Burkitt Lymphoma Catabolic Process Cell Culture Techniques Cell Death Cell Proliferation Cell Survival Cells Cessation of life Client Development Drug Metabolic Detoxication Endoplasmic Reticulum Equilibrium Excision Exhibits Family Gene Expression Gene Expression Profile Genes Genetic Growth Homeostasis Human Hypoxia In Vitro Lymphoid Lymphoma Lymphomagenesis Lysosomes Malignant Neoplasms Mediating Messenger RNA Metabolism Microarray Analysis Modeling Molecular Chaperones Mus Nutrient Oncogenes Oncogenic Ontology Organelles Oxidation-Reduction Oxidative Stress Pathway interactions Patients Phosphotransferases Property Protein Biosynthesis Proteins Proto-Oncogene Proteins c-myc Reactive Oxygen Species Recycling Reporting Role Sampling Small Interfering RNA Stress Stress and Coping Tamoxifen Testing Transgenic Mice Translating Western Blotting activating transcription factor 4 arm attenuation biological adaptation to stress c-myc Genes c-myc Proto-Oncogenes cancer cell cell transformation clinically relevant coping mechanism differential expression endoplasmic reticulum stress in vivo inhibition of autophagy insight member mouse model novel outcome forecast overexpression programs public health relevance response targeted treatment tumor tumor growth tumor initiation tumor progression tumorigenesis tumorigenic

项目摘要

DESCRIPTION (provided by applicant): The proto-oncogene c-Myc is frequently deregulated in human tumors and its overexpression associates with poor prognosis in patients. Particularly, 90% of Burkitt's lymphoma cases exhibit constitutive expression of c- Myc as a result of translocations. Considering the paradoxical role of c-Myc as an inducer of both proliferation and apoptosis, it is essential to understand how c-Myc dependent tumors disable the apoptosis arm of c-Myc while maintaining its pro-tumorigenic properties. Our group has shown that activation of the PERK-eiF2a-ATF4 arm of the Unfolded Protein Response (UPR), a protein homeostasis mechanism is required for survival of c- Myc-induced apoptosis both in vitro and in vivo, suggesting this pathway is utilized by c-Myc overexpressing cells to overcome oncogenic stress. Moreover, evidence for activation of the PERK arm of the UPR in lymphoma patient samples compared to normal B cells bolsters the clinical relevance of this pathway during c- Myc induced lymphomagenesis. However, how PERK mediates its pro-survival roles, including activation of cytoprotective autophagy, remains unexplored. Employing ATF4-/- MEFs, I have demonstrated that one of the downstream effector of PERK, ATF4, promotes survival and mediates activation of autophagy during c-Myc induction. ATF4-dependent autophagy in the context of hypoxia eliminates Reactive Oxygen Species (ROS) and accumulated proteins, recycling nutrients to fuel growth. Although ATF4 has been shown to promote survival in extrinsic stresses, it is not clear how it promotes survival during oncogene-induced, intrinsic stress. Furthermore, the augmentation of protein synthesis and unique metabolism of c-Myc driven cancer cells, makes them prone to both ER and oxidative stress. Therefore, activation of stress coping mechanisms, such as those that promote degradation of excess proteins as well as damaged organelles and promote redox homeostasis become vital to overcome oncogene induced stress. Thus, I hypothesize that ATF4 promotes survival of c-Myc overexpressing cells by inducing autophagy and suppressing oxidative stress. To test my hypothesis, I will employ both cell culture and a relevant transgenic mouse model system. The transgenic mouse model will be the first to test the role of ATF4 during tumor initiation and progression in vivo. Using this syste I can deplete ATF4 in the cell of origin of lymphomas, B-cells, in an established model of lymphoma, E¿-Myc. Additionally, I will perform microarray analysis to identify ATF4-dependent pathways during c-Myc activation. Despite the observation that ATF4 is upregulated in lymphomas, its requirement in c- Myc induced tumorigenesis in vivo has not been well studied. My study will provide insights in to mechanisms that c-Myc overexpressing cells rely on for survival and may extend to other c-Myc dependent tumors.

描述（由申请人提供）：原癌基因c-Myc在人类肿瘤中很少受到调节，其过度表达与患者的不良预后相关，特别是，90%的伯基特淋巴瘤病例由于易位而表现出c-Myc的组成型表达。考虑到 c-Myc 作为增殖和凋亡诱导剂的矛盾作用，有必要了解 c-Myc 依赖性肿瘤如何禁用凋亡臂我们的小组已经证明，未折叠蛋白反应（UPR）的 PERK-eiF2a-ATF4 臂的激活是 c-Myc 诱导的细胞凋亡存活所必需的，这是一种蛋白质稳态机制。在体外和体内，表明 c-Myc 过表达细胞利用该途径来克服致癌性此外，与正常 B 细胞相比，淋巴瘤患者样本中 UPR 的 PERK 臂激活的证据支持了该通路在 c-Myc 诱导的淋巴瘤发生过程中的临床相关性。然而，PERK 如何介导其促生存作用，包括激活。我利用 ATF4-/- MEF 证明了 PERK 的下游效应子之一 ATF4 可促进细胞保护性自噬的存活并介导其激活。在缺氧情况下，c-Myc 诱导过程中的 ATF4 依赖性自噬消除了活性氧 (ROS) 和积累的蛋白质，循环利用营养物质以促进生长。它可以促进癌基因诱导的内在应激期间的存活，此外，c-Myc 驱动的癌细胞的蛋白质合成和独特代谢的增强，使它们容易受到 ER 和氧化应激的影响。因此，激活应激应对机制，例如促进过量蛋白质和受损细胞器降解以及促进氧化还原稳态的机制对于克服癌基因诱导的应激至关重要。因此，我发现 ATF4 通过诱导 c-Myc 过表达细胞来促进存活。为了验证我的假设，我将采用细胞培养物和相关的转基因小鼠模型系统，该转基因小鼠模型将是第一个测试 ATF4 在肿瘤发生和发展过程中的作用的模型。使用该系统，我可以在已建立的淋巴瘤模型 E¿ 中耗尽淋巴瘤起源细胞（B 细胞）中的 ATF4此外，我将进行微阵列分析来识别 c-Myc 激活过程中 ATF4 依赖性途径，尽管观察到 ATF4 在淋巴瘤中上调，但其在 c-Myc 诱导的体内肿瘤发生中的需求尚未得到充分研究。将深入了解 c-Myc 过表达细胞赖以生存的机制，并可能扩展到其他 c-Myc 依赖性肿瘤。