Abstract
Activation of T cells leads to the induction of many cytokine genes that are required for appropriate immune responses, including IL-2, a key cytokine for T cell proliferation and homeostasis. The activating transcription factors such as nuclear factor of activated T cells, nuclear factor kappaB/Rel and activated protein-1 family members that regulate inducible IL-2 gene expression have been well documented. However, negative regulation of the IL-2 gene is less studied. Here we examine the role of zinc finger E-box-binding protein (ZEB) 1, a homeodomain/Zn finger transcription factor, as a repressor of IL-2 gene transcription. We show here that ZEB1 is expressed in non-stimulated and stimulated T cells and using chromatin immunoprecipitation assays we show that ZEB1 binds to the IL-2 promoter. Over-expression of ZEB1 can repress IL-2 promoter activity, as well as endogenous IL-2 mRNA production in EL-4 T cells, and this repression is dependent on the ZEB-binding site at -100. ZEB1 cooperates with the co-repressor C-terminal-binding protein (CtBP) 2 and with histone deacetylase 1 to repress the IL-2 promoter and this cooperation depends on the ZEB-binding site in the promoter as well as the Pro-X-Asp-Leu-Ser protein-protein interaction domain in CtBP2. Thus, ZEB1 may function to recruit a repressor complex to the IL-2 promoter.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Alcohol Oxidoreductases
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Animals
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Binding Sites / immunology
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Cell Line, Tumor
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Co-Repressor Proteins
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DNA-Binding Proteins / immunology
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DNA-Binding Proteins / metabolism
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Feedback, Physiological / genetics
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Feedback, Physiological / immunology
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Histone Deacetylase 1
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Histone Deacetylases / immunology
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Histone Deacetylases / metabolism
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Homeodomain Proteins / genetics
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Homeodomain Proteins / immunology*
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Homeodomain Proteins / metabolism
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Homeostasis / immunology
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Interleukin-2 / genetics*
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Interleukin-2 / immunology
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Interleukin-2 / metabolism
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Kruppel-Like Transcription Factors / genetics
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Kruppel-Like Transcription Factors / immunology*
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Kruppel-Like Transcription Factors / metabolism
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Mice
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Mice, Inbred C57BL
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Phosphoproteins / immunology
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Phosphoproteins / metabolism
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Promoter Regions, Genetic / immunology
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Protein Binding
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Protein Interaction Domains and Motifs / immunology
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Repressor Proteins / genetics
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Repressor Proteins / immunology*
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Repressor Proteins / metabolism
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T-Lymphocytes / immunology
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T-Lymphocytes / metabolism*
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Transcriptional Activation / genetics
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Transcriptional Activation / immunology
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Transfection
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Transgenes
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Zinc Finger E-box-Binding Homeobox 1
Substances
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Co-Repressor Proteins
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DNA-Binding Proteins
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Homeodomain Proteins
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Interleukin-2
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Kruppel-Like Transcription Factors
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Phosphoproteins
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Repressor Proteins
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ZEB1 protein, mouse
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Zinc Finger E-box-Binding Homeobox 1
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Alcohol Oxidoreductases
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Ctbp2 protein, mouse
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Hdac1 protein, mouse
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Histone Deacetylase 1
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Histone Deacetylases