BACKGROUND/AIMS: 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.
BACKGROUND/AIMS: 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.
Authors: Yuqing Liu; Xiao Ming Wen; Eric Lik Hang Lui; Scott L Friedman; Wei Cui; Nancy Pei Shan Ho; Lei Li; Tao Ye; Sheung Tat Fan; Hui Zhang Journal: Lab Invest Date: 2009-08-10 Impact factor: 5.662
Authors: Mark A Eckert; Miguel Santiago-Medina; Thinzar M Lwin; Jihoon Kim; Sara A Courtneidge; Jing Yang Journal: J Cell Sci Date: 2017-05-03 Impact factor: 5.285
Authors: Bryan T Hennessy; Ana-Maria Gonzalez-Angulo; Katherine Stemke-Hale; Michael Z Gilcrease; Savitri Krishnamurthy; Ju-Seog Lee; Jane Fridlyand; Aysegul Sahin; Roshan Agarwal; Corwin Joy; Wenbin Liu; David Stivers; Keith Baggerly; Mark Carey; Ana Lluch; Carlos Monteagudo; Xiaping He; Victor Weigman; Cheng Fan; Juan Palazzo; Gabriel N Hortobagyi; Laura K Nolden; Nicholas J Wang; Vicente Valero; Joe W Gray; Charles M Perou; Gordon B Mills Journal: Cancer Res Date: 2009-05-12 Impact factor: 12.701