Abstract
Transforming growth factor beta (TGFbeta) is a tumor suppressor acting as inhibitor of cell cycle progression of epithelial cells. We show that treatment of the pancreatic carcinoma cell lines PANC-1 and BxPC-3 with TGFbeta1 inhibits both growth factor-induced activation of the extracellular signal-regulated kinase 2 (ERK2) and translocation of the kinase to the nucleus. TGFbeta1 causes a concentration-dependent reduction of cell proliferation in both cell lines. By measuring ERK activation, we can show that TGFbeta1 is able to repress ERK activation induced by mitogenic stimuli such as EGF. This inhibitory effect of TGFbeta1 is not mediated by suppression of Ras or c-Raf-1 activation, but mediated by TGFbeta1-induced activation of a serine-threonine phosphatase, as demonstrated by inhibition of phosphatases by treatment with okadaic acid. Results obtained in the Smad4-deficient pancreatic carcinoma cell line BxPC-3, demonstrate that TGFbeta1-induced growth inhibition is mediated by a Smad4-independent prevention of ERK2 activation. In contrast to the effects of TGFbeta1 on epithelial cells, mesenchymal NIH3T3 fibroblasts exhibit elevated ERK2 activation and increased cell proliferation in response to TGFbeta1 treatment. Smad4-independent phosphatase-mediated inhibition of mitogen-activated ERK2 represents a novel effector pathway contributing to suppression of epithelial pancreatic carcinoma cell proliferation by TGFbeta1, in addition to the well-known Smad-induced tumor suppressor activity of TGFbeta. Oncogene (2000) 19, 4531 - 4541.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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3T3 Cells / drug effects
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3T3 Cells / metabolism
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Animals
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Biological Transport / drug effects
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Carcinoma / drug therapy
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Carcinoma / metabolism*
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Carcinoma / pathology
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Cell Cycle / drug effects
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Cell Division / drug effects
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Cell Nucleus / metabolism
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DNA-Binding Proteins / drug effects
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DNA-Binding Proteins / metabolism*
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Enzyme Activation / drug effects
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Enzyme Inhibitors / pharmacology
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Humans
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Mice
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Mitogen-Activated Protein Kinase 1 / antagonists & inhibitors
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Mitogen-Activated Protein Kinase 1 / drug effects
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Mitogen-Activated Protein Kinase 1 / metabolism*
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Okadaic Acid / pharmacology
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Pancreatic Neoplasms / drug therapy
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Pancreatic Neoplasms / metabolism*
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Pancreatic Neoplasms / pathology
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Protein Serine-Threonine Kinases
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Proto-Oncogene Proteins c-raf / metabolism
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Receptor, Transforming Growth Factor-beta Type II
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Receptors, Transforming Growth Factor beta / drug effects
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Receptors, Transforming Growth Factor beta / metabolism
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Signal Transduction
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Smad4 Protein
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Trans-Activators / drug effects
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Trans-Activators / metabolism*
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Transforming Growth Factor beta / pharmacology*
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Tumor Cells, Cultured
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ras Proteins / metabolism
Substances
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DNA-Binding Proteins
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Enzyme Inhibitors
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Receptors, Transforming Growth Factor beta
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SMAD4 protein, human
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Smad4 Protein
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Smad4 protein, mouse
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Trans-Activators
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Transforming Growth Factor beta
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Okadaic Acid
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Protein Serine-Threonine Kinases
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Proto-Oncogene Proteins c-raf
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Mitogen-Activated Protein Kinase 1
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Receptor, Transforming Growth Factor-beta Type II
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ras Proteins