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Am J Physiol Cell Physiol 281: C311-C319, 2001;
0363-6143/01 $5.00
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Vol. 281, Issue 1, C311-C319, July 2001

Smad4 mediates activation of mitogen-activated protein kinases by TGF-beta in pancreatic acinar cells

Diane M. Simeone1, Lizhi Zhang1, Kathleen Graziano1, Barbara Nicke2, Trinh Pham1, Claus Schaefer2, and Craig D. Logsdon2

Departments of 1 Surgery and 2 Physiology, University of Michigan Medical School, Ann Arbor, Michigan 48109

Transforming growth factor-beta (TGF-beta ) inhibits pancreatic acinar cell growth. In many cell types, TGF-beta mediates its growth inhibitory effects by activation of Smad proteins. Recently, it has been reported that Smad proteins may interact with the mitogen-activated protein (MAP) kinase signaling pathways. In this study, we report on the interactions between the TGF-beta and MAP kinase signaling pathways in isolated rat pancreatic acinar cells. TGF-beta activated the MAP kinases extracellular signal-related kinases (ERKs) and p38 in pancreatic acinar cells, but had no effect on c-jun NH2-terminal kinase activity. Activation of MAP kinase by TGF-beta was maximal 4 h after treatment. The ability of TGF-beta to activate ERKs was concentration dependent and dependent on protein synthesis. TGF-beta 's stimulation of ERK activation was blocked by PD-98059, an inhibitor of MAP kinase kinase 1, and by adenoviral transfer of dominant negative RasN17. Furthermore, adenoviral-mediated expression of dominant negative Smad4 blocked the ability of TGF-beta to activate acinar cell MAP kinase, demonstrating that this activation is downstream of Smads. The biological relevance of ERK activation by TGF-beta was indicated by demonstrating that inhibition of ERK signaling by PD-98059 blocked the ability of TGF-beta to activate the transcription factor activator protein-1. These studies provide new insight into the signaling mechanisms by which TGF-beta mediates biological actions in pancreatic acinar cells.

transforming growth factor-beta


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