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Inhibition of rat hepatocyte proliferation by transforming growth factor beta and glucagon is associated with inhibition of ERK2 and p70 S6 kinase

Lookup NU author(s): Professor Loranne Agius, Emeritus Professor Steve Yeaman, Professor Chris Day


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Stimulation of hepatocyte proliferation by epidermal growth factor (ECF) and insulin is inhibited by transforming growth factor beta (TGF-beta) and by glucagon, It is also suppressed by inhibitors of various protein kinases, including rapamycin, which blocks activation of p70 S6 kinase (p70(S6k)), PD98059, which inhibits the activation of extracellular-regulated kinase (ERK), and SE 203580, an inhibitor of the p38 mitogen-activated protein kinase (p38 MAPK), In this study, we investigated whether the inhibition of proliferation by TGF-beta involves these protein kinase cascades. Culture of hepatocytes with TGF-beta for 16 hours decreased the stimulation by EGF of ERK2 and p70(56k) (by 50% and 35%, respectively), but did not affect the stimulation of either p38 MAPK, c-jun NH2-terminal kinase (JNK), or protein kinase B (PKB). Culture of hepatocytes with glucagon for 16 hours also inhibited the stimulation by EGF of activation of ERK2 and p70(S6k) (by approximate to 50%). The inhibitory effects of glucagon were observed when the hormone was added either 10 minutes or 60 minutes before EGF addition, whereas no effects of TGF-beta were observed after 10-minute or 60-minute incubation. These results suggest that the inhibition of hepatocyte proliferation by TGF-beta may be in part mediated by inhibition of ERK2 and p7056k, but does not involve PKB, JNK, or p38 MAPK. Unlike glucagon, the effects of TGF-beta are not elicited in response to short-term treatment.

Publication metadata

Author(s): Day CP; Yeaman SJ; Agius L; Dixon M

Publication type: Article

Publication status: Published

Journal: Hepatology

Year: 1999

Volume: 29

Issue: 5

Pages: 1418-1424

Print publication date: 01/05/1999

ISSN (print): 0270-9139

ISSN (electronic): 1527-3350

Publisher: John Wiley & Sons, Inc.


DOI: 10.1002/hep.510290516


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