Abstract
In addition to acting as a hematopoietic growth factor, interleukin-4 (IL-4) inhibits growth of some transformed cells in vitro and in vivo. In this study, we show that insulin receptor substrate (IRS)-1, IRS-2, and signal transducer and activator of transcription 6 (STAT6) are phosphorylated following IL-4 treatment in MCF-7 breast cancer cells. STAT6 DNA binding is enhanced by IL-4 treatment. STAT6 activation occurs even after IRS-1 depletion, suggesting the two pathways are independent. To examine the role of STAT6 in IL-4-mediated growth inhibition and apoptosis, a full-length STAT6 cDNA was transfected into MCF-7 cells. Transient overexpression of STAT6 resulted in both cytoplasmic and nuclear expression of the protein, increased DNA binding in response to IL-4, and increased transactivation of an IL-4 responsive promoter. In STAT6-transfected cells, basal proliferation was reduced whereas apoptosis was increased. Finally, stable expression of STAT6 resulted in reduced foci formation compared to vector-transfected cells alone. These results suggest STAT6 is required for IL-4-mediated growth inhibition and induction of apoptosis in human breast cancer cells.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Adenocarcinoma / metabolism
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Adenocarcinoma / pathology*
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Apoptosis / drug effects
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Apoptosis / physiology
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Breast Neoplasms / metabolism
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Breast Neoplasms / pathology*
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Cell Division / drug effects
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Cell Division / physiology
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DNA, Complementary / genetics
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Female
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Growth Inhibitors / pharmacology*
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Humans
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Insulin Receptor Substrate Proteins
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Interleukin-4 / pharmacology*
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Intracellular Signaling Peptides and Proteins
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Neoplasm Proteins / physiology*
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Phosphoproteins / metabolism
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Phosphorylation
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Protein Processing, Post-Translational / drug effects
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Recombinant Fusion Proteins / physiology
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STAT6 Transcription Factor
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Signal Transduction
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Trans-Activators / genetics
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Trans-Activators / physiology*
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Transcriptional Activation
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Transfection
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Tumor Cells, Cultured / drug effects
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Tumor Cells, Cultured / pathology
Substances
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DNA, Complementary
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Growth Inhibitors
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IRS1 protein, human
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IRS2 protein, human
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Insulin Receptor Substrate Proteins
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Intracellular Signaling Peptides and Proteins
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Neoplasm Proteins
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Phosphoproteins
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Recombinant Fusion Proteins
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STAT6 Transcription Factor
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STAT6 protein, human
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Trans-Activators
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Interleukin-4