Abstract
Collagenase-3 (MMP-13) is characterized by an exceptionally wide substrate specificity and restricted expression. MMP-13 is specifically expressed by transformed human keratinocytes in squamous cell carcinomas in vivo and its expression correlates with their invasion capacity. Here, we show, that interferon-gamma (IFN-gamma) markedly inhibits expression of MMP-13 by human cutaneous SCC cells (UT-SCC-7) and by ras-transformed human epidermal keratinocytes (A-5 cells) at the transcriptional level. In addition, IFN-gamma inhibits collagenase-1 (MMP-1) expression in these cells. IFN-gamma abolished the enhancement of MMP-13 and MMP-1 expression by transforming growth factor-beta (TGF-beta) and tumor necrosis factor-alpha (TNF-alpha), and inhibited invasion of A-5 cells through type I collagen. IFN-gamma also rapidly and transiently activates extracellular signal-regulated kinase 1,2 (ERK1,2) and blocking ERK1,2 pathway (Raf/MEK1,2/ERK1,2) by specific MEK1,2 inhibitor PD98059 partially (by 50%) prevents Ser-727 phosphorylation of STAT1 and suppression of MMP-13 expression by IFN-gamma. Furthermore, Ser-727 phosphorylation of STAT1 by ERK1,2, or independently of ERK1,2 activation is associated with marked reduction in MMP-13 expression. These observations identify a novel role for IFN-gamma as a potent inhibitor of collagenolytic activity and invasion of transformed squamous epithelial cells, and show that inhibition of MMP-13 expression by IFN-gamma involves activation of ERK1,2 and STAT1.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Cell Line, Transformed
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Cell Survival / drug effects
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Cell Transformation, Neoplastic / drug effects*
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Cell Transformation, Neoplastic / metabolism*
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Collagenases / biosynthesis*
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Collagenases / genetics
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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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Interferon-gamma / pharmacology*
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Keratinocytes / drug effects
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Keratinocytes / enzymology*
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Keratinocytes / metabolism
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Matrix Metalloproteinase 13
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Matrix Metalloproteinase Inhibitors*
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Matrix Metalloproteinases / biosynthesis*
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Matrix Metalloproteinases / genetics
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Mitogen-Activated Protein Kinase 1 / metabolism*
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Mitogen-Activated Protein Kinase 3
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Mitogen-Activated Protein Kinases / metabolism*
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Organ Specificity / genetics
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Recombinant Proteins
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STAT1 Transcription Factor
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Trans-Activators / metabolism*
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Transcription, Genetic / drug effects
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Transcription, Genetic / genetics
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Transforming Growth Factor beta / antagonists & inhibitors
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Tumor Cells, Cultured
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Tumor Necrosis Factor-alpha / antagonists & inhibitors
Substances
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DNA-Binding Proteins
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Enzyme Inhibitors
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Matrix Metalloproteinase Inhibitors
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Recombinant Proteins
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STAT1 Transcription Factor
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STAT1 protein, human
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Trans-Activators
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Transforming Growth Factor beta
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Tumor Necrosis Factor-alpha
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Interferon-gamma
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Mitogen-Activated Protein Kinase 1
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Mitogen-Activated Protein Kinase 3
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Mitogen-Activated Protein Kinases
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Collagenases
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MMP13 protein, human
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Matrix Metalloproteinase 13
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Matrix Metalloproteinases