Abstract
Accumulating evidence has shown the importance of Stat6-mediated signaling in allergic diseases. In this study, we show a novel regulatory mechanism of Stat6-mediated signaling in mast cells. When Stat6 is activated by interleukin (IL)-4 and translocated to the nucleus, Stat6 is cleaved by a nucleus-associated protease in mast cells. The cleaved 65-kD Stat6 lacks the COOH-terminal transactivation domain and functions as a dominant-negative molecule to Stat6-mediated transcription. The retrovirus-mediated expression of cleavage-resistant Stat6 mutants prolongs the nuclear accumulation of Stat6 upon IL-4 stimulation and enhances IL-4-induced gene expression and growth inhibition in mast cells. These results indicate that the proteolytic processing of Stat6 functions as a lineage-specific negative regulator of Stat6-dependent signaling in mast cells, and thus suggest that it may account for the limited role of Stat6 in IL-4 signaling in mast cells.
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 / drug effects
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COS Cells
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Cell Division / drug effects
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Cell Nucleus / metabolism
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Cells, Cultured
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DNA-Binding Proteins / metabolism
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Feedback, Physiological / physiology*
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Genes, Dominant
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Interleukin-4 / genetics
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Interleukin-4 / metabolism
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Interleukin-4 / pharmacology
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Mast Cells / cytology
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Mast Cells / drug effects
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Mast Cells / metabolism*
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Milk Proteins*
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Mutagenesis, Site-Directed
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Phosphorylation
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Protein Isoforms / deficiency
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Protein Isoforms / genetics
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Protein Isoforms / metabolism
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Protein Processing, Post-Translational / physiology*
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Receptors, IgE / metabolism
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Retroviridae / genetics
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STAT5 Transcription Factor
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STAT6 Transcription Factor
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Serine Endopeptidases / drug effects
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Serine Endopeptidases / metabolism
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Serine Proteinase Inhibitors / pharmacology
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Signal Transduction / physiology*
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Trans-Activators / deficiency
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Trans-Activators / genetics
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Trans-Activators / metabolism*
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Transcription, Genetic / physiology
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Transfection
Substances
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DNA-Binding Proteins
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Milk Proteins
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Protein Isoforms
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Receptors, IgE
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STAT5 Transcription Factor
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STAT6 Transcription Factor
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Serine Proteinase Inhibitors
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Stat6 protein, mouse
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Trans-Activators
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Interleukin-4
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Serine Endopeptidases