A systematical analysis of the signal transduction pathways induced by the Latent Membrane Protein 1 (LMP1) of Epstein-Barr virus.

To systematically investigate mechanisms of signal transduction by the EBV oncogene LMP1, the time-dependent regulation of cellular signaling pathways by inducible LMP1 variants was studied in mouse embryonic fibroblasts lacking expression of signaling molecules. This led to insights into the importance of cellular TRAF6 and TRADD for LMP1 signaling, and specifically uncovered indirect activation of STAT3 mediated by the LMP1-dependent secretion of the inflammatory cytokine LIF. The relevance of the presented results for carcinogenesis was addressed in NPC cells and EBV-transformed B cells

The Latent Membrane Protein 1 (LMP1).

Almost exactly twenty years after the discovery of Epstein-Barr virus (EBV), the latent membrane protein 1 (LMP1) entered the EBV stage, and soon thereafter, it was recognized as the primary transforming gene product of the virus. LMP1 is expressed in most EBV-associated lymphoproliferative diseases and malignancies, and it critically contributes to pathogenesis and disease phenotypes. Thirty years of LMP1 research revealed its high potential as a deregulator of cellular signal transduction pathways leading to target cell proliferation and the simultaneous subversion of cell death programs. However, LMP1 has multiple roles beyond cell transformation and immortalization, ranging from cytokine and chemokine induction, immune modulation, the global alteration of gene and microRNA expression patterns to the regulation of tumor angiogenesis, cell-cell contact, cell migration, and invasive growth of tumor cells. By acting like a constitutively active receptor, LMP1 recruits cellular signaling molecules associated with tumor necrosis factor receptors such as tumor necrosis factor receptor-associated factor (TRAF) proteins and TRADD to mimic signals of the costimulatory CD40 receptor in the EBV-infected B lymphocyte. LMP1 activates NF-κB, mitogen-activated protein kinase (MAPK), phosphatidylinositol 3-kinase (PI3-K), IRF7, and STAT pathways. Here, we review LMP1's molecular and biological functions, highlighting the interface between LMP1 and the cellular signal transduction network as an important factor of virus-host interaction and a potential therapeutic target