A mechanism in Epstein-Barr virus oncogenesis: inhibition of transforming growth factor-beta 1-mediated induction of MAPK/p21 by LMP1.
Epstein-Barr virus (EBV)-infected, gastric epithelial cell line GT38 is resistant to TGF-beta 1-mediated growth inhibition and apoptosis, although TGF-beta 1 partially induces EBV reactivation in the cells. These findings indicate that abnormalities exist in these cells in the TGF-beta 1-mediated signaling pathway, influencing growth inhibition and apoptosis. In order to characterize the steps with abnormalities, we analyzed the TGF-beta 1/MAPK/p21 pathway in the cells. TGF-beta 1 activated MAPK (ERK 1/2) and p21 in the TGF-beta 1-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-beta 1-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-kappa B activation in LMP1-transfected HSC-39 cells, which then became resistant to TGF-beta 1-mediated growth inhibition, TGF-beta 1-mediated ERK 1/2 phosphorylation, and p21 induction, and proliferated in low-serum medium. These results are consistent with the conclusion that the TGF-beta 1/MAPK/p21 pathway is required for TGF-beta 1-mediated growth inhibition, and that the resistance to TGF in GT38 cells is derived from constitutive MAPK phosphorylation induced by LMP1.
Fukuda
Makoto
M
Department of Biosignaling, School of Life Science, Faculty of Medicine, Tottori University, Yonago 683-8505, Japan.
Kurosaki
Wataru
W
Yanagihara
Kazuyoshi
K
Kuratsune
Hirohiko
H
Sairenji
Takeshi
T
D002461:Cell Line, Transformed; D002471:Cell Transformation, Neoplastic; D002472:Cell Transformation, Viral; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000378:metabolism*; D005786:Gene Expression Regulation; D004854:Herpesvirus 4, Human / Q000472:pathogenicity* / Q000502:physiology; D006801:Humans; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors* / Q000378:metabolism; D053773:Transforming Growth Factor beta1; D014407:Tumor Cells, Cultured; D014763:Viral Matrix Proteins / Q000378:metabolism*
C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; C037662:EBV-associated membrane antigen, Epstein-Barr virus; C508960:TGFB1 protein, human; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D014763:Viral Matrix Proteins; D020928:Mitogen-Activated Protein Kinases