Abstract
Many of the actions of serine/threonine kinase receptors for the transforming growth factor-beta (TGFbeta) are mediated by DPC4, a human MAD-related protein identified as a tumor suppressor gene in pancreatic carcinoma. Overexpression of DPC4 is sufficient to induce the activation of gene expression and cell cycle arrest, characteristic of the TGFbeta response. The stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK) is also one of the downstream targets required for TGFbeta-mediated signaling. Here we report that expression of the dominant-interfering mutant of various components of the SAPK/JNK cascade specifically blocked both TGFbeta and DPC4-induced gene expression. These dominant-interfering mutants also inhibited TGFbeta-stimulated DPC4 transcriptional activity. Moreover, we find that overexpression of DPC4 causes transfected cells to undergo the morphological changes typical of apoptosis. These findings define a mechanism whereby TGFbeta signals mediated by DPC4 and SAPK/JNK cascade are integrated in the nucleus to activate gene expression and identify a new cellular function for DPC4.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Apoptosis*
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Calcium-Calmodulin-Dependent Protein Kinases / metabolism*
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Cell Line
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DNA-Binding Proteins*
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Dogs
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Genes, Reporter
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Genes, Tumor Suppressor
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Humans
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JNK Mitogen-Activated Protein Kinases
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MAP Kinase Kinase 1
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Mitogen-Activated Protein Kinase Kinases*
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Mitogen-Activated Protein Kinases*
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Protein Serine-Threonine Kinases / metabolism*
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Protein-Tyrosine Kinases / metabolism*
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Proto-Oncogene Proteins c-jun / metabolism
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Recombinant Fusion Proteins / metabolism
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Signal Transduction / drug effects
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Smad4 Protein
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Trans-Activators / metabolism*
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Transcription, Genetic / drug effects
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Transfection
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Transforming Growth Factor beta / pharmacology*
Substances
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DNA-Binding Proteins
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Proto-Oncogene Proteins c-jun
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Recombinant Fusion Proteins
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SMAD4 protein, human
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Smad4 Protein
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Trans-Activators
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Transforming Growth Factor beta
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Protein-Tyrosine Kinases
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Protein Serine-Threonine Kinases
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Calcium-Calmodulin-Dependent Protein Kinases
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JNK Mitogen-Activated Protein Kinases
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Mitogen-Activated Protein Kinases
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MAP Kinase Kinase 1
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MAP2K1 protein, human
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Mitogen-Activated Protein Kinase Kinases