title: Active repression of IFN regulatory factor-1-mediated transactivation by IFN regulatory factor-4.
abstract: IFN regulatory factor-4 (IRF-4) is a transcription factor that is involved in the development and the functions of lymphocytes, macrophages and dendritic cells. Despite their critical roles in immune system regulation, the target genes controlled by IRF-4 are poorly understood. In this study, we determined the consensus DNA-binding sequences preferred for IRF-4 by in vitro binding site selections. IRF-4 preferentially bound to the sequences containing tandem repeats of 5'-GAAA-3', flanked by CpC, in most cases. IRF-4 repressed the promoter bearing tandem copies of the selected binding sequence, while IRF-1 activated the same constructs. Interestingly, the IRF-1-dependent transactivation is inhibited in the presence of IRF-4, but not IRF-2. A series of deletion mutants of IRF-4 revealed that its DNA-binding domain was necessary and sufficient to antagonize the IRF-1-dependent transactivation. This dominant negative action of IRF-4 over IRF-1 was also observed in a natural promoter context, such as the TRAIL gene. These results indicate that IRF-4 acts as a natural antagonist against IRF-1 in immune cells.
authors.affiliation: Division of Cytokine Signaling, Department of Molecular Microbiology and Immunology, Nagasaki University Graduate School of Biomedical Sciences, 1-12-4 Sakamoto, Nagasaki 852-8523, Japan.
authors.forename: Kayo
authors.initials: K
authors.lastname: Yoshida
authors.forename: Kazuo
authors.initials: K
authors.lastname: Yamamoto
authors.forename: Tomoko
authors.initials: T
authors.lastname: Kohno
authors.forename: Noriko
authors.initials: N
authors.lastname: Hironaka
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Yasui
authors.forename: Chojiro
authors.initials: C
authors.lastname: Kojima
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Mukae
authors.forename: Jun-ichi
authors.initials: J
authors.lastname: Kadota
authors.forename: Shoichi
authors.initials: S
authors.lastname: Suzuki
authors.forename: Kiri
authors.initials: K
authors.lastname: Honma
authors.forename: Shigeru
authors.initials: S
authors.lastname: Kohno
authors.forename: Toshifumi
authors.initials: T
authors.lastname: Matsuyama
mesh_terms: D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000276:immunology; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology; D005786:Gene Expression Regulation / Q000235:genetics / Q000276:immunology*; D006367:HeLa Cells; D006801:Humans; D050856:Interferon Regulatory Factor-1 / Q000235:genetics / Q000276:immunology*; D050835:Interferon Regulatory Factors / Q000235:genetics / Q000276:immunology*; D008214:Lymphocytes / Q000276:immunology; D008264:Macrophages / Q000276:immunology; D008562:Membrane Glycoproteins / Q000235:genetics / Q000276:immunology; D050436:Regulatory Elements, Transcriptional / Q000235:genetics / Q000276:immunology*; D017384:Sequence Deletion / Q000235:genetics; D053221:TNF-Related Apoptosis-Inducing Ligand; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000276:immunology; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology*; D000099218:Interferon Regulatory Factor-4
chemical_list: D051017:Apoptosis Regulatory Proteins; D050856:Interferon Regulatory Factor-1; D050835:Interferon Regulatory Factors; D008562:Membrane Glycoproteins; D053221:TNF-Related Apoptosis-Inducing Ligand; D014409:Tumor Necrosis Factor-alpha; D000099218:Interferon Regulatory Factor-4; C494257:IRF1 protein, human; C505653:TNFSF10 protein, human