Abstract
The proinflammatory cytokine tumor necrosis factor (TNF) alpha is mainly produced in cells from the monocyte/macrophage lineage. TNFalpha is also a key signaling molecule in the liver functioning as an important physiological and pathogenic mediator. In hepatocytes or human hepatoma cells TNFalpha is expressed at extremely low levels but TNFalpha biosynthesis can be induced by interleukin (IL)-1beta or 12-O-tetradecanoylphorbol-13-acetate (TPA). Here, we show that IL-1beta and TPA stimulated TNFalpha gene transcription in hepatoma cells mediated by a composite TPA-responsive element/cAMP response element. Both IL-1beta and TPA triggered phosphorylation and activation of the basic region leucine zipper transcription factors c-Jun and ATF2 and expression of dominant-negative mutants of c-Jun and ATF2-reduced TNFalpha promoter activity and secretion of TNFalpha. Expression of the nuclear dual-specific MAP kinase phosphatase-1 (MKP-1) blocked TNFalpha promoter activity and TNFalpha secretion following IL-1beta or TPA stimulation, indicating that MKP-1 functions as a nuclear shut-of-device of IL-1beta and TPA-induced TNFalpha expression.
2006 Wiley-Liss, Inc.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Activating Transcription Factor 2 / genetics
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Activating Transcription Factor 2 / metabolism*
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Carcinoma, Hepatocellular / metabolism
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Cell Cycle Proteins / genetics
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Cell Cycle Proteins / metabolism
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Cell Line, Tumor
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Dual Specificity Phosphatase 1
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Enzyme Activation
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Gene Expression Regulation, Neoplastic
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Humans
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Immediate-Early Proteins / genetics
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Immediate-Early Proteins / metabolism
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Interleukin-1beta / pharmacology*
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JNK Mitogen-Activated Protein Kinases / genetics
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JNK Mitogen-Activated Protein Kinases / metabolism*
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Liver Neoplasms / metabolism
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MAP Kinase Kinase 6 / genetics
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MAP Kinase Kinase 6 / metabolism
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Phosphoprotein Phosphatases / genetics
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Phosphoprotein Phosphatases / metabolism
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Phosphorylation
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Promoter Regions, Genetic
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Protein Phosphatase 1
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Protein Tyrosine Phosphatases / genetics
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Protein Tyrosine Phosphatases / metabolism
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Response Elements
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Tetradecanoylphorbol Acetate / pharmacology*
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Tumor Necrosis Factor-alpha / biosynthesis*
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Tumor Necrosis Factor-alpha / genetics
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p38 Mitogen-Activated Protein Kinases / genetics
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p38 Mitogen-Activated Protein Kinases / metabolism*
Substances
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ATF2 protein, human
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Activating Transcription Factor 2
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Cell Cycle Proteins
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Immediate-Early Proteins
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Interleukin-1beta
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Tumor Necrosis Factor-alpha
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JNK Mitogen-Activated Protein Kinases
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p38 Mitogen-Activated Protein Kinases
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MAP Kinase Kinase 6
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Phosphoprotein Phosphatases
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Protein Phosphatase 1
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DUSP1 protein, human
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Dual Specificity Phosphatase 1
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Protein Tyrosine Phosphatases
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Tetradecanoylphorbol Acetate