The lab focuses primarily on the mechanism of function of latent membrane protein 1(LMP1) and certain tumor necrosis factor receptors (TNFRs). LMP1 is the principal transforming protein of Epstein-Barr virus (EBV) and is tightly associated with the development of several EBV-associated human malignancies including nasopharyngeal carcinoma, Hodgkin's disease, immunoblastic lymphomas of immunosuppressed patients and gastric carcinomas. Our work has demonstrated that LMP1 functions as a constitutively active cell surface receptor that mimics the mechanism of action of certain tumor necrosis factor receptors (TNFRs). TNFRs regulate a wide spectrum of cellular functions related to inflammatory and immune responses, apoptosis and tumor growth. We have shown that signal transduction by LMP1 and certain TNFRs (CD40, CD30, LTβR, TNFRI and TNFRII) involves members of the TRAF family of signal transducers which are recruited to LMP1 or activated TNFRs. TRAF1, TRAF2, TRAF3, TRAF5 and TRAF6 have been implicated in LMP1 signal transduction. However the precise role of each one of these molecules in the function of LMP1 remains unknown. Our lab employs the yeast two-hybrid method and biochemical purification approaches to dissect the molecular steps of LMP1 signaling downstream from the recruitment of TRAF molecules. We have demonstrated that TRAF6, IRAK1 AND IKKbeta are essential for NF-κB activation by LMP1, in general. We are currently investigating the role of TRAF1, TRAF2, TRAF3, TRAF5 and other molecules in NF-κB-dependent activation of specific genes by LMP1. Furthermore, we are using transgenic and gene knock-out mouse models to analyze the function of LMP1 and other transforming factors of EBV in vivo. The molecular mechanism of LMP1 signal transduction is compared to the mechanism of signaling by selected TNFRs such as CD40. Our long-term goal is the identification of novel targets for therapeutic approaches of malignancies and immune system disorders associated with LMP1 and TNFRs.