Details

Autor(en) / Beteiligte

• Le Pabic, Hélène
• L'Helgoualc'h, Annie
• Coutant, Alexandre
• Wewer, Ulla M.
• Baffet, Georges
• Clément, Bruno
• Théret, Nathalie

Titel

Involvement of the serine/threonine p70 S6 kinase in TGF-β1-induced ADAM12 expression in cultured human hepatic stellate cells

Ist Teil von

• Journal of hepatology, 2005, Vol.43 (6), p.1038-1044

Ort / Verlag

Elsevier B.V

Erscheinungsjahr

2005

Link zum Volltext

Quelle

Elsevier ScienceDirect Journals Complete

Beschreibungen/Notizen

• In chronic liver injury, quiescent hepatic stellate cells change into proliferative myofibroblast-like cells, which are a main source of fibrosis. We have recently reported that these cells synthesize ADAM12, a disintegrin and metalloprotease whose expression is up-regulated by TGF-β1 in liver cancers. Here, we studied the role of the serine/threonine p70 S6 kinase (p70 S6K) in regulating TGF-β1-induced ADAM12 expression. The phophatidylinositol 3-kinase (PI3K) inhibitor LY294002 and the mitogen-activated protein kinase inhibitor, UO126, decreased the TGF-β1-dependent ADAM12 expression and prevented the phosphorylation of p70 S6K. In addition, TGF-β1-induced ADAM12 up-regulation was blocked by the Frap/mTOR inhibitor rapamycin, which abrogated the phosphorylation of p70 S6K. In untreated cells, LY294002 but not rapamycin diminished the basal ADAM12 expression related to inhibition of Akt and the glycogen synthase kinase-3 phosphorylation. The data suggest that TGF-β1 induces ADAM12 gene expression through both the PI3K/Frap-mTOR/p70 S6K and MEK/ERK pathways. In addition, activation of the PI3 pathway might be involved in the basal ADAM12 expression in cultured hepatic stellate cells. The involvement of PI3K in ADAM12 expression, similar to that previously observed for collagen I and fibronectin, suggests common pathways for gene up-regulation in hepatic stellate cells that occur during liver fibrogenesis and contribute to tumor progression.