[Frontiers in Bioscience 7, d319-329, January 1, 2002] 319 CELLULAR SIGNALING PATHWAYS ENGAGED BY THE EPSTEIN-BARR VIRUS TRANSFORMING PROTEIN LMP1 Eudoxia Hatzivassiliou 1 and George Mosialos 2 1 Department of Biology, Aristotle University of Thessaloniki, Thessaloniki 54006, Greece, 2 Institute of Immunology, Biomedical Sciences Research Center Al. Fleming, 14-16 Al. Fleming Str., Vari 16672, Greece TABLE OF CONTENTS 1. Abstract 2. Introduction 3. Structural and functional elements of LMP1 4. The NF-κB pathway 5. The AP1 pathway 6. The JAK/STAT pathway 7. LMP1 is a viral pseudoreceptor of the TNFR superfamily 8. Perspectives 9. Acknowledgments 10. References 1. ABSTRACT The latent membrane protein 1 (LMP1) of Epstein-Barr virus (EBV) is an essential component of the viral machinery that orchestrates cellular transformation and oncogenesis. The critical role of LMP1 in transformation has been established through recombinant genetic analysis of the EBV genome, ectopic expression in cell lines and transgenic mice and immunohistochemical analysis of EBV- associated tumor specimens. The principal mechanism of LMP1 function is based on mimicry of activated cell surface receptors of the tumor necrosis factor superfamily. LMP1 signaling culminates in the activation of transcription factors NF-κB, AP1 and STAT1/3, which have been tightly linked to prevention of apoptosis and malignant transformation. The molecular mechanisms of LMP1 function will be reviewed in this report. 2. INTRODUCTION Epstein-Barr virus (EBV) is a highly prevalent human herpesvirus, which infects epithelial cells and B- lymphocytes and it has been associated with a number of human malignancies (1). The infection of epithelial cells is primarily lytic whereas the infection of B-lymphocytes is usually latent thus allowing the virus to establish a persistent infection. In healthy individuals EBV is restricted by the immune system to a very small number of memory B-lymphocytes that does not exceed approximately 50 cells per one million of peripheral blood B-lymphocytes (2, 3). To avoid further the immune surveillance the virus expresses only two out of nine antigens that represent the full spectrum of latent antigen gene expression (4-7). The delicate balance that is established between the virus and the immune system allows the infection to persist for the life of the host. However in immune deficient patients EBV may escape from the strict control of the immune system and express up to 10 latent genes most of which have been implicated in the process of tumorigenesis (8). The oncogenic factors of EBV have been identified through the recombinant genetic analysis of the viral genome coupled with EBV-mediated growth transformation of primary B-lymphocytes in vitro into long-term proliferating lymphoblastoid cell lines (LCL) (8). These studies have demonstrated that the latent EBV antigens LMP1, EBNA2, EBNALP, EBNA3A and EBNA3C are essential for the process of B cell transformation in vitro. EBNA1 is required for the maintenance of the viral genome in latently infected cells and its direct involvement in the process of transformation could not be addressed in these studies. The transforming potential of EBV latent antigens has been evaluated further through the phenotypic analysis of cells expressing individual antigens and immunohistochemical characterization of EBV-associated tumor specimens. All the evidence accumulated so far support a role for LMP1 as the principal transforming factor of EBV. LMP1 is essential for EBV-mediated B lymphocyte transformation in vitro since viral strains lacking LMP1 expression are unable to transform B-lymphocytes (9). LMP1 is expressed in most human malignancies associated with EBV,