title: JunD/AP-1 and STAT3 are the major enhancer molecules for high Bcl6 expression in germinal center B cells.
abstract: The Bcl6 proto-oncogene, which encodes a transcriptional repressor, is ubiquitously expressed and predominantly in germinal center (GC) B cells. Although the promoter region of the human Bcl6 gene has been reported, enhancer molecules for its high expression in GC B cells were largely unknown. Here we show that transcriptional start sites of the murine Bcl6 gene were different from the reported human one. DNA sequence around the new promoter region is highly conserved between mice and humans and has no canonical TATA or CCAAT box. Two AP-1-binding elements in the promoter region were the major enhancer elements in GC-derived B lymphoma cells, and JunD/AP-1 was detected in GC B cells. In addition, we identified the silencer region with three Bcl6-binding elements around the start site. Bcl6 bound to the silencer elements and its over-expression repressed the promoter activity through the elements. Activated STAT factors (STATs), especially activated STAT3, also bound to the silencer elements in GC B cells and competed with Bcl6 for the binding, suggesting that JunD/AP-1 and activated STATs drive high Bcl6 expression in GC B cells. Since stimulation of splenic B cells with IL-4 or IL-21 induced high Bcl6 expression with induction of junD and activation of STATs, these cytokines may be inducers for its high expression in GC B cells. However, IL-21 but not IL-4 stimulation activated STAT3 in splenic B cells. Thus, IL-21 may be a major inducer for high Bcl6 expression in GC B cells.
authors.affiliation: Department of Developmental Genetics (H2), Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan.
authors.forename: Eggi
authors.initials: E
authors.lastname: Arguni
authors.forename: Masafumi
authors.initials: M
authors.lastname: Arima
authors.forename: Nobuhide
authors.initials: N
authors.lastname: Tsuruoka
authors.forename: Akemi
authors.initials: A
authors.lastname: Sakamoto
authors.forename: Masahiko
authors.initials: M
authors.lastname: Hatano
authors.forename: Takeshi
authors.initials: T
authors.lastname: Tokuhisa
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000276:immunology*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000276:immunology*; D016758:Genes, jun / Q000276:immunology*; D018858:Germinal Center / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D015847:Interleukin-4 / Q000276:immunology / Q000494:pharmacology; D007378:Interleukins / Q000276:immunology / Q000494:pharmacology; D051379:Mice; D000090063:Proto-Oncogene Mas; D051560:Proto-Oncogene Proteins c-bcl-6; D050796:STAT3 Transcription Factor / Q000276:immunology / Q000378:metabolism; D037941:Silencer Elements, Transcriptional / Q000276:immunology; D013045:Species Specificity; D013154:Spleen / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D016385:TATA Box / Q000276:immunology; D018808:Transcription Factor AP-1 / Q000276:immunology* / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects / Q000276:immunology; D000098546:Interleukin-21
chemical_list: C490010:Bcl6 protein, mouse; D004268:DNA-Binding Proteins; D007378:Interleukins; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D051560:Proto-Oncogene Proteins c-bcl-6; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D018808:Transcription Factor AP-1; D015847:Interleukin-4; D000098546:Interleukin-21