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

• 批准号: 9186519
• 负责人: Feven Tameire
• 金额: $ 3.09万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-12-13 至 2017-12-12
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9186519
• 关键词: Ablation; Allografting; Amino Acids; Analysis of Variance; Antioxidants; Apoptosis; Attenuated; Autophagocytosis; B-Lymphocytes; Biological Assay; Biological Models; Biological Process; Burkitt Lymphoma; C-Myc Translocation; 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; Genetic Transcription; Growth; Homeostasis; Human; Hypoxia; In Vitro; Lymphoid; Lymphoma; Lymphomagenesis; Lysosomes; Malignant Neoplasms; Mediating; Messenger RNA; Metabolism; Microarray Analysis; Modeling; Molecular Chaperones; Mus; NOVA2 gene; Nutrient; Oncogenes; Oncogenic; Ontology; Organelles; Oxidation-Reduction; Oxidative Stress; Pathway interactions; Patients; Pharmacology; 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; Tumorigenicity; 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; new therapeutic target; outcome forecast; overexpression; programs; proteostasis; public health relevance; response; therapeutic target; tumor; tumor growth; tumor initiation; tumor progression; tumorigenesis; tumorigenic

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(申请人提供)：原癌基因c-Myc在人类肿瘤中经常被解除调控，其过度表达与患者的不良预后有关。特别是，90%的Burkitt淋巴瘤病例由于易位而表现出c-Myc的结构性表达。考虑到c-Myc作为增殖和凋亡诱导者的矛盾作用，了解c-Myc依赖的肿瘤如何在保持其促肿瘤特性的同时禁用c-Myc的凋亡臂是至关重要的。我们的团队已经证明，激活未折叠蛋白反应(UPR)的perk-eiF2a-ATF4臂是c-Myc诱导的细胞凋亡在体外和体内存活所必需的蛋白质稳态机制，这表明c-Myc过表达的细胞利用这一途径来克服致癌 压力。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这一途径在c-Myc诱导的淋巴瘤发生中的临床相关性。然而，PERK如何调节其促生存作用，包括激活细胞保护性自噬，仍未被探索。利用ATF4-/-MEF，我已经证明了PERK的下游效应之一ATF4在c-Myc诱导过程中促进存活并介导自噬的激活。在低氧环境下，依赖ATF4的自噬消除了活性氧物种(ROS)和积累的蛋白质，回收营养物质以促进生长。虽然ATF4已被证明能促进外在压力下的存活，但尚不清楚它是如何在癌基因诱导的内在应激中促进存活的。此外，c-Myc驱动的癌细胞蛋白质合成和独特代谢的增强，使它们容易受到内质网和氧化应激的影响。因此，激活应激应对机制，如促进过剩蛋白质和受损细胞器的降解以及促进氧化还原动态平衡，对于克服癌基因诱导的应激至关重要。因此，我假设ATF4通过诱导自噬和抑制氧化应激来促进c-Myc过表达细胞的存活。为了验证我的假设，我将同时使用细胞培养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在体内肿瘤发生和发展过程中的作用的动物模型。使用这个系统，我可以去除淋巴瘤起源细胞中的ATF4，在已建立的淋巴瘤模型E�-Myc中，B细胞。此外，我将进行微阵列分析，以确定c-Myc激活过程中依赖ATF4的途径。尽管观察到ATF4在淋巴瘤中表达上调，但它在c-Myc诱导的体内肿瘤发生中的作用还没有得到很好的研究。我的研究将为c-Myc过度表达细胞生存所依赖的机制提供见解，并可能延伸到其他依赖c-Myc的肿瘤。