Modulation of Apoptosis by IRF-4 in EBV transformation

IRF-4 在 EBV 转化中对细胞凋亡的调节

• 批准号: 7756516
• 负责人: LUWEN ZHANG
• 金额: $ 27.29万
• 依托单位: UNIVERSITY OF NEBRASKA LINCOLN
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-04 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7756516
• 关键词: Acquired Immunodeficiency Syndrome; Address; Apoptosis; Apoptotic; B-Lymphocytes; Binding; Burkitt Lymphoma; C-terminal; Caspase; Caspase Inhibitor; Cells; Central Nervous System Lymphoma; Chromosomal translocation; Consensus; DNA Binding Domain; DNA Sequence; Development; Down-Regulation; Epstein-Barr Virus Infections; Equilibrium; Family; Family member; Gene Targeting; Genes; Goals; Growth; Human; Human Herpesvirus 4; Human T-Cell Leukemia Viruses; IRF4 gene; In Vitro; Interferon Regulatory Factor 4; Interferons; Lead; Lymphoma; Malignant Neoplasms; Mediating; Methods; Mitochondria; Multiple Myeloma; N-terminal; Names; Oncogenic; Pathway interactions; Patients; Plasmids; Play; Prevention; Process; Role; TP53 gene; Tumor Suppressor Proteins; Viral; Viral Proteins; Virus; cell growth; cell transformation; cytokine; in vivo; member; new therapeutic target; prevent; research study; restoration; therapeutic target; tumor

Epstein-Barr virus (EBV) infection is an important cause of lymphomas in AIDS patients, especially in central nervous system lymphoma (CNS lymphoma). EBV transforms human primary B cells in vitro, the process of which is believed to resemble EBV transformation in vivo in AIDS-associated CNS lymphoma. How EBV regulates cellular genes to achieve the transformation remains unclear. Interferon regulatory factor-4 (IRF-4) is a member of the IRF family that has oncogenic potential. IRF-4 is highly expressed in EBV-transformed primary B cells in vitro, and high IRF-4 expression is associated with EBV in primary CNS lymphomas. Furthermore, down-regulation of IRF-4 results in apoptosis in EBV-transformed cells, and restore the IRF-4 expression prevented the growth inhibition of endogenous IRF4-kncokdown cells. Thus, IRF-4 is a critical factor involved in EBV-transformation, and a potential therapeutic target for EBV-associated tumors in vivo; however, the anti-apoptotic mechanism of IRF-4 in EBV transformation is unknown. Our long-term goal is to understand the role of cellular factors in viral transformation. The more immediate goal of this application is to determine the anti-apoptotic mechanisms of IRF-4 in EBV-transformed B lymphocytes. Apoptosis is roughly classified as intrinsic and extrinsic pathways. EBV induces some anti-apoptotic Bcl-2 family members that are capable of prevention of the intrinsic apoptosis pathway, and uses several viral proteins to block the functions of p53, a potential intrinsic pathway inducer. We thus hypothesize that an intrinsic apoptosis pathway may be activated but blocked by IRF-4 during EBV transformation. We will determine the mitochondria integrity and some hallmark caspase activities after IRF-4-knockdown to distinguish the two pathways. Whether specific inhibitors of caspases and other critical molecules involved in apoptosis rescue IRF-4-knockdown cells from apoptosis will be examined. These experiments may identify the apoptosis. These experiments may identify critical mechanisms that IRF-4 uses to prevent apoptosis in EBV-transformed cells.

爱泼斯坦 - 巴尔病毒（EBV）感染是艾滋病患者淋巴瘤的重要原因，尤其是中枢神经系统淋巴瘤（CNS淋巴瘤）。 EBV在体外转化了人类原代B细胞，该过程被认为与AIDS相关的CNS淋巴瘤中的体内类似于EBV转化。 EBV如何调节细胞基因以实现转化尚不清楚。干扰素调节因子-4（IRF-4）是具有致癌潜力的IRF家族的成员。 IRF-4在EBV转换的原代B细胞体外高度表达，并且高IRF-4表达与原代CNS淋巴瘤中的EBV相关。此外，IRF-4的下调导致EBV转换细胞的凋亡，并恢复IRF-4表达，阻止了内源性IRF4-KNCOKDOWN细胞的生长抑制。因此，IRF-4是与EBV转化有关的关键因素，也是体内与EBV相关肿瘤的潜在治疗靶点。但是，IRF-4在EBV转化中的抗凋亡机制尚不清楚。我们的长期目标是了解细胞因子在病毒转化中的作用。该应用的更直接的目标是确定EBV转化的B淋巴细胞中IRF-4的抗凋亡机制。细胞凋亡大致归类为固有和外在途径。 EBV诱导了一些能够预防内在凋亡途径的抗凋亡Bcl-2家族成员，并使用多种病毒蛋白来阻止p53的功能，p53是潜在的固有途径诱导剂。因此，我们假设固有的凋亡途径可以被激活，但在EBV转化过程中被IRF-4阻塞。我们将确定IRF-4敲击后的线粒体完整性和一些标志性的caspase活动，以区分这两种途径。是否会检查胱天蛋白酶抑制剂和凋亡中涉及的其他关键分子从凋亡中拯救IRF-4敲低细胞。这些实验可以鉴定凋亡。这些实验可能会确定IRF-4用于预防EBV转化细胞凋亡的关键机制。