11401854

pubmed:Citation

1

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.

eng

IM

MEDLINE

0363-6143

Print

NLM

C311-9

pubmed-meshheading:11401854-Adenoviridae, pubmed-meshheading:11401854-Animals, pubmed-meshheading:11401854-Cholecystokinin, pubmed-meshheading:11401854-Cycloheximide, pubmed-meshheading:11401854-DNA-Binding Proteins, pubmed-meshheading:11401854-Enzyme Activation, pubmed-meshheading:11401854-Enzyme Inhibitors, pubmed-meshheading:11401854-Flavonoids, pubmed-meshheading:11401854-Genes, Reporter, pubmed-meshheading:11401854-Immunoblotting, pubmed-meshheading:11401854-MAP Kinase Kinase 1, pubmed-meshheading:11401854-MAP Kinase Signaling System, pubmed-meshheading:11401854-Mitogen-Activated Protein Kinase Kinases, pubmed-meshheading:11401854-Mitogen-Activated Protein Kinases, pubmed-meshheading:11401854-Pancreas, pubmed-meshheading:11401854-Protein Binding, pubmed-meshheading:11401854-Protein Synthesis Inhibitors, pubmed-meshheading:11401854-Protein-Serine-Threonine Kinases, pubmed-meshheading:11401854-Rats, pubmed-meshheading:11401854-Rats, Wistar, pubmed-meshheading:11401854-Smad4 Protein, pubmed-meshheading:11401854-Trans-Activators, pubmed-meshheading:11401854-Transcription Factor AP-1, pubmed-meshheading:11401854-Transforming Growth Factor beta, pubmed-meshheading:11401854-p38 Mitogen-Activated Protein Kinases, pubmed-meshheading:11401854-ras Proteins

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

Journal Article, In Vitro, Research Support, U.S. Gov't, P.H.S., Research Support, Non-U.S. Gov't