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: 8652136
• 负责人: Feven Tameire
• 金额: $ 4.22万
• 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/8652136
• 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; endoplasmic reticulum stress; in vivo; inhibition of autophagy; insight; member; mouse model; novel; outcome forecast; overexpression; programs; public health relevance; response; 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（由申请人提供）：原癌基因c-Myc在人类肿瘤中经常失调，其过表达与患者预后不良相关。特别地，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，理解c-Myc依赖性肿瘤如何使c-Myc的凋亡臂失效同时保持其促肿瘤发生特性是至关重要的。我们的小组已经表明，未折叠蛋白应答（UPR）的PERK-eIF 2a-ATF 4臂的激活，一种蛋白质稳态机制，是体外和体内c-Myc诱导的凋亡的存活所必需的，表明该途径被c-Myc过表达细胞利用以克服致癌性细胞凋亡。 应力 此外，与正常B细胞相比，淋巴瘤患者样品中UPR的PERK臂活化的证据支持了该途径在c-Myc诱导的淋巴瘤发生期间的临床相关性. 然而，PERK如何介导其促生存作用，包括细胞保护性自噬的激活，仍然未被探索。采用ATF 4-/- MEFs，我已经证明了PERK的下游效应子之一ATF 4在c-Myc诱导期间促进存活并介导自噬的激活。 在缺氧的情况下，ATF 4依赖性自噬消除了活性氧（ROS）和积累的蛋白质，回收营养物质以促进生长。 虽然ATF 4已被证明可以促进外源性应激中的存活，但尚不清楚它如何促进癌基因诱导的内源性应激中的存活。 此外，c-Myc驱动的癌细胞的蛋白质合成和独特代谢的增加使它们易于ER和氧化应激。因此，激活应激应对机制，如促进过量蛋白质以及受损细胞器的降解和促进氧化还原稳态的机制，对于克服癌基因诱导的应激变得至关重要。因此，我推测ATF 4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，我将采用细胞培养和相关的转基因小鼠模型系统。 转基因小鼠模型将是第一个测试ATF 4在体内肿瘤发生和发展过程中的作用的模型。 使用这个系统，我可以在淋巴瘤的起源细胞，B细胞，在一个建立的淋巴瘤模型，E-Myc中耗尽ATF 4。 此外，我将进行微阵列分析，以确定在c-Myc激活过程中ATF 4依赖的途径。尽管观察到ATF 4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.我的研究将为c-Myc过表达细胞生存所依赖的机制提供见解，并可能扩展到其他c-Myc依赖性肿瘤。