Unique Signaling Properties of CTAR1 in LMP1-Mediated Transformation

Abstract

The Epstein-Barr virus (EBV) latent membrane protein 1 (LMP1) gene is considered the EBV oncogene as it is necessary for EBV-mediated transformation of B lymphocytes and itself transforms rodent fibroblasts. LMP1 activates the NF-B, phosphatidylinositol 3-kinase (PI3K)-Akt, mitogen-activated protein kinase, and Jun N-terminal protein kinase signaling pathways through its two signaling domains, carboxyl-terminal activating regions 1 and 2 (CTAR1 and CTAR2). CTAR1 and CTAR2 induce signal transduction pathways through their direct (CTAR1) or indirect (CTAR2) recruitment of tumor necrosis factor receptor-associated factors (TRAFs). CTAR1 is necessary for LMP1-mediated transformation as well as activation of PI3K signaling and induction of cell cycle markers associated with G 1 /S transition. In this study, activation of PI3K-Akt signaling and deregulation of cell cycle markers were mapped to the TRAF-binding domain within CTAR1 and to the residues between CTAR1 and CTAR2. LMP1 CTAR1 also activated the MEK1/2-extracellular signal-regulated kinase 1/2 signaling pathway, and this activation was necessary for LMP1-induced transformation of Rat-1 fibroblasts. Dominant-negative forms of TRAF2 and TRAF3 inhibited but did not fully block LMP1-mediated transformation. These findings identify a new signaling pathway that is uniquely activated by the TRAF-binding domain of LMP1 and is required for transformation.

Epstein-Barr Virus Downregulates MicroRNA 203 through the Oncoprotein Latent Membrane Protein 1: a Contribution to Increased Tumor Incidence in Epithelial Cells

“…EBV and LMP1 facilitate the G 1 /S transition in cell cycle progression and transformation (32,33,51). In the present study, overexpression of miR-203 blocks the G 1 /S transition in EBV-infected cells and suppresses tumor growth in vivo (Fig.…”

Human tumor virus utilizes exosomes for intercellular communication

“…Cell monolayers were washed twice with PBS and incubated with purified exosomes (200-400 μg) or PBS for the indicated times at 37°C in serum-free media. Cells exposed to exosomes were washed three times with PBS, scraped into cold PBS, pelleted, and lysed in radioimmunoprecipitation assay (RIPA) buffer (20). Subconfluent Rat-1 cells were exposed to conditioned, clarified media from C33A cells every 24 h for 5 d.…”

“…Transformation of Rat1 cells by LMP1 requires activation of PI3K and ERK (20). To determine the effects of C33A exosomes in untransformed cells, Rat-1 fibroblasts were exposed to purified LMP1 exosomes, control exosomes, or PBS.…”

Infection of Epstein–Barr virus in a gastric carcinoma cell line induces anchorage independence and global changes in gene expression

“…The LMP1 DN construct contains mutations of amino acids 204-208 to A as well as Y348G (37). shLMP1-1 and shLMP1-2 plasmids express a hairpin RNA with a 19-mer stem, targeting sequences that have been successfully used to knock down LMP1 (38,39).…”