The transcription repressor, ZEB1, cooperates with CtBP2 and HDAC1 to suppress IL-2 gene activation in T cells.
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.
Wang
Jun
J
Division of Molecular Bioscience, John Curtin School of Medical Research, Australian National University, Canberra, ACT 2601 Australia.
Lee
Seungsoo
S
Teh
Charis En-Yi
CE
Bunting
Karen
K
Ma
Lina
L
Shannon
M Frances
MF
D000429:Alcohol Oxidoreductases; D000818:Animals; D001665:Binding Sites / Q000276:immunology; D045744:Cell Line, Tumor; D056970:Co-Repressor Proteins; D004268:DNA-Binding Proteins / Q000276:immunology / Q000378:metabolism; D025461:Feedback, Physiological / Q000235:genetics / Q000276:immunology; D056284:Histone Deacetylase 1; D006655:Histone Deacetylases / Q000276:immunology / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D006706:Homeostasis / Q000276:immunology; D007376:Interleukin-2 / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D010750:Phosphoproteins / Q000276:immunology / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000276:immunology; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs / Q000276:immunology; D012097:Repressor Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D015533:Transcriptional Activation / Q000235:genetics / Q000276:immunology; D014162:Transfection; D019076:Transgenes; D000071799:Zinc Finger E-box-Binding Homeobox 1
D056970:Co-Repressor Proteins; D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; D007376:Interleukin-2; D051741:Kruppel-Like Transcription Factors; D010750:Phosphoproteins; D012097:Repressor Proteins; C519422:ZEB1 protein, mouse; D000071799:Zinc Finger E-box-Binding Homeobox 1; D000429:Alcohol Oxidoreductases; C111341:Ctbp2 protein, mouse; C484389:Hdac1 protein, mouse; D056284:Histone Deacetylase 1; D006655:Histone Deacetylases