Hepatitis b virus x protein inhibits transforming growth factor-β-induced apoptosis through the activation of phosphatidylinositol 3-kinase pathway
Journal
Journal of Biological Chemistry
Journal Volume
275
Journal Issue
33
Pages
25858-25864
Date Issued
2000
Author(s)
Abstract
Transforming growth factor·β (TGF-β) is a potent inducer of apoptosis in Hep 3B cells. This work investigated how hepatitis B virus X protein (HBx) affects TGFβ-induced apoptosis. Trypan blue exclusion and colony formation assays revealed that HBx increased the ID50 toward TGF-β. In the presence of HBx, TGF-β-induced DNA laddering was decreased, indicating that HBx had the ability to block TGF-β-induced apoptosis. Furthermore, HBx did not alter the expression levels of type I and type II TGF-β receptors. HBx did not affect TGF-βinduced activation of promoter activities of the plasminogen activator inhibitor-1 (PAI-1) gene. These results indicate that HBx interferes with only a subset of TGF-β activity. In the presence of phosphatidylinositol (PI) 3-kinase inhibitors, wortmannin or LY294002, the HBxmediated inhibitory effect on TGF-β-induced apoptosis was alleviated. In addition, the tyrosine phosphorylation levels of the regulatory subunit p85 of phosphatidylinositol 3-kinase (PI 3-kinase) and PI 3-kinase activity were elevated in stable clones with HBx expression. Transactivation-deficient mutants of HBx lost their ability to inhibit TGF-β-induced apoptosis. Phosphorylation of the p85 subunit of PI 3-kinase and Akt, a downstream target of PI 3-kinase, was not observed in stable clones with transactivation-deficient HBx mutant's expression. Thus, the anti-apoptotic effect of HBx against TGF-β can be mediated through the activation of the PI 3-kinase signaling pathway, and the transactivation function of HBx is required for its anti-apoptosis activity.
Other Subjects
phosphatidylinositol 3 kinase; transforming growth factor beta; virus protein; apoptosis; article; enhancer region; enzyme activation; enzyme activity; enzyme inhibition; Hepatitis B virus; human; human cell; malignant transformation; priority journal; promoter region; protein synthesis inhibition; signal transduction; target cell; transactivation; transcription regulation; 1-Phosphatidylinositol 3-Kinase; Androstadienes; Apoptosis; Arabidopsis Proteins; Cell Survival; Chromones; Culture Media, Serum-Free; DNA Fragmentation; Dose-Response Relationship, Drug; Enzyme Activation; Enzyme Inhibitors; Humans; Luciferases; Morpholines; Plant Proteins; Plasmids; Potassium Channels; Precipitin Tests; Terminal Repeat Sequences; Time Factors; Trans-Activation (Genetics); Trans-Activators; Transfection; Transforming Growth Factor beta; Tumor Cells, Cultured; Hepatitis B virus
Type
journal article