EBV Conference 2008 Guangzhou - Baylor College of Medicine

145 (RegID: 1730)
Che-Pei (Pat) Kung
Institution: University of North Carolina at Chapel Hill
e-mail: cpkung@email.unc.edu
EPSTEIN-BARR VIRUS LATENT MEMBRANE PROTEIN 1 INDUCES EPIDERMAL
GROWTH FACTOR RECEPTOR THROUGH DISTINCT NF-κB PATHWAY
Che-Pei Pat Kung and Nancy Raab-Traub
Posterabstract:
Epstein Barr virus (EBV) latent membrane protein 1 (LMP1) activates multiple forms of NF-κB through
two domains in its carboxy terminus, CTAR1 and CTAR2. The canonical pathway is regulated by IkBα
to produce the p50/p65 heterodimers and is activated by both domains. The non-canonical pathway
which produces p52/relB heterodimers and is regulated by IKKα is activated solely by CTAR1. However,
the roles of other NF-κB members, such as p50 and Bcl-3, in LMP1-mediated signaling pathways are not
well understood. We have previously shown that CTAR1 uniquely induces expression of the epidermal
growth factor receptor (EGFR), and p50/Bcl-3 complexes can be detected by chromatin
immunoprecipitation(ChIP)analysis on the EGFR promoter in CTAR1-expressing epithelial cells and
NPC cells. We show here that C33A cells expressing CTAR1 but not CTAR2 had abundant nuclear p50
and increased levels of Bcl-3. Bcl-3 was increased mainly through transcriptional induction rather than
stabilization, indicated by RT-PCR and cycloheximide/MG132 analyses. Interestingly, LMP1 CTAR1 but
not CTAR2 uniquely increased levels of phosphorylated STAT3, which is known to regulate Bcl-3
transcriptionally. Moreover, chemical inhibition of STAT3 significantly decreased Bcl-3 and EGFR. In
CTAR1 cells, increased levels of activated STAT3 were detected by ChIP on STAT-binding sites located
within both the promoter and second intron of Bcl-3. The roles of the different IKKs in EGFR induction
were also assessed using mouse embryonic fibroblasts (MEFs). Preliminary results indicate that NIK,
and to lesser level IKKα and IKKβ, are required for LMP1-mediated EGFR induction in MEFs. These
data suggest that LMP1 activates distinct forms of NF-kB to regulate different cellular genes. In addition
to the canonical and non-canonical pathways, LMP1-CTAR1 induces EGFR by constitutively activating
STAT3 and increasing Bcl-3 and this particular pathway is at least partially mediated through NIK.
EBV Conference 2008 Guangzhou
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