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.
Epstein-Barr virus (EBV) infection is a leading cause of lymphomas in humans, and the methods by which EBV regulates cellular genes is still unclear. We have found a cellular factor named IRF-4 to be critical for viral transformation;this project will address the methods by which IRF-4 regulates EBV transformation processes. The study will reveal the mechanisms used by EBV to modulate cellular factors for cancer formation, and it may provide novel therapeutic targets to treat and prevent EBV- associated lymphomas.
