Interferon-alpha-induced mTOR activation is an anti-hepatitis C virus signal via the phosphatidylinositol 3-kinase-Akt-independent pathway
| Autor: | Hironori Yamasaki, Kazuhiko Nakao, Azusa Matsumoto, Eisuke Ozawa, Katsumi Eguchi, Satoshi Miuma, Shigeyuki Takeshita, Hisamitsu Miyaaki, Motohisa Akiyama, Kumi Hirano, Masanori Ikeda, Tatsuki Ichikawa, Hidetaka Shibata, Masumi Fujimito, Nobuyuki Kato |
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| Rok vydání: | 2008 |
| Předmět: |
Hepacivirus
Phosphatidylinositol 3-Kinases Interferon alpha-2 Antiviral Agents Cell Line eIF-2 Kinase Interferon Cell Line Tumor medicine Humans Phosphorylation PI3K/AKT/mTOR pathway Janus Kinases Sirolimus EIF-2 kinase biology Dose-Response Relationship Drug TOR Serine-Threonine Kinases RPTOR Gastroenterology Interferon-alpha PKR Protein kinase R Recombinant Proteins STAT1 Transcription Factor Biochemistry HCV Cancer research biology.protein mTOR Hepatocytes STAT-1 Signal transduction Janus kinase Protein Kinases Proto-Oncogene Proteins c-akt medicine.drug Signal Transduction |
| Zdroj: | Journal of gastroenterology. 44(8) |
| ISSN: | 0944-1174 |
| Popis: | OBJECT: The interferon-induced Jak-STAT signal alone is not sufficient to explain all the biological effects of IFN. The PI3-K pathways have emerged as a critical additional component of IFN-induced signaling. This study attempted to clarify that relationship between IFN-induced PI3-K-Akt-mTOR activity and anti-viral action. RESULT: When the human normal hepatocyte derived cell line was treated with rapamycin (rapa) before accretion of IFN-alpha, tyrosine phosphorylation of STAT-1 was diminished. Pretreatment of rapa had an inhibitory effect on the IFN-alpha-induced expression of PKR and p48 in a dose dependent manner. Rapa inhibited the IFN-alpha inducible IFN-stimulated regulatory element luciferase activity in a dose-dependent manner. However, wortmannin, LY294002 and Akt inhibitor did not influence IFN-alpha inducible luciferase activity. To examine the effect of PI3-K-Akt-mTOR on the anti-HCV action of IFN-alpha, the full-length HCV replication system, OR6 cells were used. The pretreatment of rapa attenuated its anti-HCV replication effect in comparison to IFN-alpha alone, whereas the pretreatment with PI3-K inhibitors, wortmannin and LY294002 and Akt inhibitor did not influence IFN-induced anti-HCV replication. CONCLUSION: IFN-induced mTOR activity, independent of PI3K and Akt, is the critical factor for its anti-HCV activity. Jak independent mTOR activity involved STAT-1 phosphorylation and nuclear location, and then PKR is expressed in hepatocytes. Journal of Gastroenterology, 44(8), pp.856-863; 2009 |
| Databáze: | OpenAIRE |
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