We also found that HGF induces cell cycle progression, cell proliferation, apoptosis and increase in cell size in a c-Myc-dependent manner. Activation of MAPK and PI3K, inhibition of GSK-3 beta and translocation of beta-catenin to the nucleus as well as Tcf/Lef transcriptional activity were involved in mediating c-Myc induction by HGF. Induction of Cdk2 kinase activity was involved

in mediating the cell cycle progression effects, and downregulation of Bcl-XL was involved in mediating the proapoptotic effects of HGF downstream of c-Myc. All molecules that mediated the effects of HGF on c-Myc expression, cell proliferation and apoptosis were expressed in human large-cell medulloblastoma tissues. We therefore established AZD9291 purchase for the first time a functional cooperation between HGF/c-Met and c-Myc in human medulloblastoma and elucidated the molecular mechanisms of this cooperation. The findings provide

a potential explanation for the high frequency of c-Myc overexpression in medulloblastoma and suggest GW4869 molecular weight a cooperative role for c-Met and c-Myc in large-cell anaplastic medulloblastoma formation.”
“The relationship between bile duct damage and portal fibrosis in chronic liver diseases remains unclear. This study was designed to show whether human intrahepatic biliary epithelial cells can undergo epithelial -mesenchymal cell transition, thereby directly contributing to fibrogenesis. Primary human cholangiocytes no were stimulated with transforming growth factor-beta (TGF beta) or TGF beta-presenting T cells and examined for evidence of transition to a mesenchymal phenotype. Liver sections were labelled to detect antigens associated with biliary epithelial cells (cytokeratin 7 and 19 and E-cadherin), T cells (CD8), epithelial -mesenchymal transition (S100A4, vimentin and matrix metalloproteinase-2 (MMP-2)), myofibroblasts

(alpha-smooth muscle actin) and intracellular signal-transduction mediated by phosphorylated (p) Smad 2/3; in situ hybridisation was performed to detect mRNA encoding TGF beta and S100A4. Stimulation of cultured cells with TGF beta induced the expression of pSmad2/3, S100A4 and alpha-smooth muscle actin; these cells became highly motile. Although normal bile ducts expressed ALK5 (TGF beta RI), low levels of TGF beta mRNA and nuclear pSmad2/3, they did not express S100A4, vimentin or MMP-2. However, TGFb mRNA and nuclear pSmad2/3 were strongly expressed in damaged ducts, which also expressed S100A4, vimentin and MMP-2. Fibroblast-like cells which expressed S100A4 were present around many damaged bile ducts. Cells in the ‘ductular reaction’ expressed both epithelial and mesenchymal markers together with high levels of TGF beta mRNA and pSmad2/3.