Involvement of the serine/threonine p70S6 kinase in TGF-beta1-induced ADAM12 expression in cultured human hepatic stellate cells.
OBJECTIVE
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-beta1 in liver cancers. Here, we studied the role of the serine/threonine p70S6 kinase (p70S6K) in regulating TGF-beta1-induced ADAM12 expression.


RESULTS
The phophatidylinositol 3-kinase (PI3K) inhibitor LY294002 and the mitogen-activated protein kinase inhibitor, UO126, decreased the TGF-beta1-dependent ADAM12 expression and prevented the phosphorylation of p70S6K. In addition, TGF-beta1-induced ADAM12 up-regulation was blocked by the Frap/mTOR inhibitor rapamycin, which abrogated the phosphorylation of p70S6K. In untreated cells, LY294002 but not rapamycin diminished the basal ADAM12 expression related to inhibition of Akt and the glycogen synthase kinase-3 phosphorylation.


CONCLUSIONS
The data suggest that TGF-beta1 induces ADAM12 gene expression through both the PI3K/Frap-mTOR/p70S6K 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.
Le Pabic
Hélène
H
INSERM U620, Détoxication et Réparation Tissulaire, Facultés de Médecine et Pharmacie, Université de Rennes I, IFR no. 140, 2 Av. Léon Bernard, 35043 Rennes Cedex, France.
L'Helgoualc'h
Annie
A
Coutant
Alexandre
A
Wewer
Ulla M
UM
Baffet
Georges
G
Clément
Bruno
B
Théret
Nathalie
N
D051722:ADAM Proteins / Q000235:genetics* / Q000378:metabolism; D000072199:ADAM12 Protein; D002478:Cells, Cultured; D015870:Gene Expression; D006801:Humans; D008099:Liver / Q000166:cytology; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism*; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D053773:Transforming Growth Factor beta1
D008565:Membrane Proteins; C508960:TGFB1 protein, human; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D019869:Phosphatidylinositol 3-Kinases; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D020930:MAP Kinase Kinase Kinases; D051722:ADAM Proteins; D000072199:ADAM12 Protein; C000606480:ADAM12 protein, human