EBV Conference 2008 Guangzhou - Baylor College of Medicine

126 (RegID: 1152)
Kathy Ho Yen Shair
Institution: University of North Carolina at Chapel Hill, Lineberger Comprehensive Cancer Center
e-mail: khys2@email.unc.edu
THE LATENT MEMBRANE PROTEIN-1 OF EBV PROMOTES CELL GROWTH AND
MIGRATION THROUGH ACTIVATION OF AKT, NF-kB AND DOWN-REGULATION OF
PLAKOGLOBIN
Kathy H.Y Shair, Caroline Schnegg and Nancy Raab-Traub.
Posterabstract:
Latent membrane protein 1 (LMP1) is considered the major oncoprotein of EBV and is frequently
expressed in nasopharyngeal carcinomas (NPC). LMP1 activates multiple signaling pathways including
PI3K/Akt, NF-kB, JNK, p38, and ERK of which PI3K/Akt and ERK signaling are required for
LMP1-induced transformation of rodent fibroblasts. C666-1 is the only cell line established from NPC
that has retained the EBV episome. LMP1 is expressed at very low levels in these cells, however,
exogenous expression of LMP1 enhances growth and induces migration of C666 cells. To identify the
signaling pathways required for these growth effects, LMP1 and deletion mutants were expressed in C666
cells. LMP1-enhanced growth, as assayed by soft agar colony formation and MTS activity, required both
of its signaling domains, CTAR1 and CTAR2. Activation of PI3K/Akt and NF-kB signaling by
full-length LMP1 were both required and chemical inhibitors of these pathways blocked these effects.
The requirement for the canonical NFkB pathway was confirmed using an IkBa (SS32/36AA)
super-repressor. The potential metastatic properties induced by LMP1 were assessed using a transwell
migration assay. Full-length LMP1 enhanced migration and this effect also required PI3K/Akt and
canonical NFkB signaling. The LMP1-enhanced migration was linked to the transcriptional
down-regulation of plakoglobin in that migration was impaired by restoring plakoglobin expression.
Plakoglobin is a junctional protein found at adherens junctions and desmosomes and can also serve as a
transcription factor that regulates Tcf/Lef-mediated transcription. Assessment of adherens junction and
desmosome assembly, Tcf/Lef activated transcription, and the components of the transcription complexes
indicated that the plakoglobin-mediated inhibition of migration was due to junctional loss of plakoglobin
and not to transcriptional effects. These findings reveal that the profound effects of LMP1 on epithelial
cell growth and migration require activation of PI3K/Akt and NFkB signaling. The finding that LMP1
induces a loss of plakoglobin that results in enhanced migration reveals that LMP1 has multiple effects on
cell-adhesion and growth that contributes to EBV-induced oncogenesis.
EBV Conference 2008 Guangzhou
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