A mechanism in epstein-barr virus oncogenesis: Inhibition of transforming growth factor-β1-mediated induction of MAPK/p21 by LMP1

Abstract

Epstein-Barr virus (EBV)-infected, gastric epithelial cell line GT38 is resistant to TGF-β1-mediated growth inhibition and apoptosis, although TGF-β1 partially induces EBV reactivation in the cells. These findings indicate that abnormalities exist in these cells in the TGF-β1-mediated signaling pathway, influencing growth inhibition and apoptosis. In order to characterize the steps with abnormalities, we analyzed the TGF-β1/MAPK/p21 pathway in the cells. TGF-β1 activated MAPK (ERK 1/2) and p21 in the TGF-β1-susceptible cell line HSC-39 but not in GT38 cells. GT38 cells had higher constitutive levels of ERK 1/2 phosphorylation and p21 expression than did HSC-39 cells. U0126, a specific inhibitor of MEK, suppressed TGF-β1-mediated ERK 1/2 phosphorylation and p21 induction in HSC-39 cells and constitutive ERK 1/2 phosphorylation in GT38 cells. EBV latent membrane protein 1 (LMP1) induced constitutive ERK 1/2 phosphorylation and NF-κB activation in LMP1-transfected HSC-39 cells, which then became resistant to TGF-β1-mediated growth inhibition, TGF-β1-mediated ERK 1/2 phosphorylation, and p21 induction, and proliferated in low-serum medium. These results are consistent with the conclusion that the TGF-β1/MAPK/p21 pathway is required for TGF-β1-mediated growth inhibition, and that the resistance to TGF in GT38 cells is derived from constitutive MAPK phosphorylation induced by LMP1. © 2002 Elsevier Science (USA).