<> "The repository administrator has not yet configured an RDF license."^^ . <> . . "Impact of HBV and HCV Infection on TGF-beta signaling"^^ . "HCC is the most common type of cancer, often induced by viral infection with hepatitis B virus (HBV) or hepatitis C virus (HCV). Transforming growth factor-β (TGF-β) is an important cytokine upon liver damage as in wound healing and liver fibrosis due to its proapoptotic, antiproliferative and immunosuppressive functions on the epithelium. This work investigated the impact of HBV and HCV infection on TGF-β dependent signaling, its outcome and on the progression of chronic liver disease to HCC.\r\ncDNA microarrays were generated of primary human hepatocytes (PHHs) infected with HBV and treated with TGF-β for 1 and 24hrs, respectively. Gene expression analysis revealed that HBV regulated p53 and mTOR signaling pathway, the latter one known as being downstream of the Akt survival signaling pathway. Upon TGF-β treatment, HBV infection abrogated TGF-β signaling in PHHs and reduced the number of TGF-β regulated target genes. HepG2.2.15 cells, which replicate HBV, show decreased Smad3 phosphorylation and transcriptional activity, and impaired TGF-β induced apoptosis. HBV replication increased Akt phosphorylation, but deactivation of Akt by its specific inhibitor LY294002 sensitized HepG2.2.15 cells for TGF-β induced apoptosis. This effect was Smad3 independent. TGF-β induced apoptosis upon Akt deactivation could be reduced by p38 MAPK inhibitor SB203580.\r\nTo investigate the impact of HCV on TGF-β signaling, Huh7 cells were stably transfected with HCV core protein (Huh7-HCV core cells). In these cells, TGF-β dependent Smad3 phosphorylation and transcriptional activity were reduced, TGF-β induced apoptosis was abolished, and TGF-β target genes involved in cell cycle arrest, like GADD45β, p15, and p21 were downregulated. HCV core protein further induced expression of the pro-fibrotic cytokine connective tissue growth factor (CTGF), which was however TGF-β independent.\r\nIn summary, the data of this thesis suggest, that HBV infection and HCV core protein interfere with canonical TGF-β signaling. Upon HBV infection, survival signaling pathways are induced, which counteract TGF-β signaling. Replication of HBV and overexpression of HCV core protein blunted Smad3 signaling and TGF-β induced apoptosis was abrogated. These results indicate that viral infection facilitates the escape of hepatocytes from the TGF-β induced apoptosis to assure viral survival in the hepatocytes.\r\n"^^ . "2014" . . . . . . . "Jasmin"^^ . "Fabian"^^ . "Jasmin Fabian"^^ . . . . . . "Impact of HBV and HCV Infection on TGF-beta signaling (PDF)"^^ . . . "Thesis_final_Jasmin Fabian.pdf"^^ . . . "Impact of HBV and HCV Infection on TGF-beta signaling (Other)"^^ . . . . . . "indexcodes.txt"^^ . . . "Impact of HBV and HCV Infection on TGF-beta signaling (Other)"^^ . . . . . . "small.jpg"^^ . . . "Impact of HBV and HCV Infection on TGF-beta signaling (Other)"^^ . . . . . . "medium.jpg"^^ . . . "Impact of HBV and HCV Infection on TGF-beta signaling (Other)"^^ . . . . . . "preview.jpg"^^ . . . "Impact of HBV and HCV Infection on TGF-beta signaling (Other)"^^ . . . . . . "lightbox.jpg"^^ . . "HTML Summary of #16655 \n\nImpact of HBV and HCV Infection on TGF-beta signaling\n\n" . "text/html" . .