title: Regulation of c-Fos gene expression by NF-κB: a p65 homodimer binding site in mouse embryonic fibroblasts but not human HEK293 cells.
abstract: The immediate early gene c-Fos is reported to be regulated by Elk-1 and cAMP response element-binding protein (CREB), but whether nuclear factor (NF)-κB is also required for controlling c-Fos expression is unclear. In this study, we determined how NF-κB's coordination with Elk/serum response factor (SRF) regulates c-fos transcription. We report that PMA strongly induced c-Fos expression, but tumor necrosis factor (TNF)-α did not. In mouse embryonic fibroblasts, the PMA induction of c-Fos was suppressed by a deficiency in IKKα, IKKβ, IKKγ, or p65. By contrast, in human embryonic kidney 293 cells, PMA induced c-Fos independently of p65. In accordance with these results, we identified an NF-κB binding site in the mouse but not human c-fos promoter. Under PMA stimulation, IKKα/β mediated p65 phosphorylation and the binding of the p65 homodimer to the NF-κB site in the mouse c-fos promoter. Furthermore, our studies demonstrated independent but coordinated functions of the IKKα/β-p65 and extracellular signal-regulated kinase (ERK)-Elk-1 pathways in the PMA induction of c-Fos. Collectively, these results reveal the distinct requirement of NF-κB for mouse and human c-fos regulation. Binding of the p65 homodimer to the κB site was indispensable for mouse c-fos expression, whereas the κB binding site was not present in the human c-fos promoter. Because of an inability to evoke sufficient ERK activation and Elk-1 phosphorylation, TNF-α induces c-Fos more weakly than PMA does in both mouse and human cells.
authors.affiliation: Department of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Yu-Cheng
authors.initials: YC
authors.lastname: Tu
authors.affiliation: Department of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Duen-Yi
authors.initials: DY
authors.lastname: Huang
authors.affiliation: National Institute of Cancer Research, National Health Research Institutes, Zhunan, Miaoli County, Taiwan.
authors.forename: Shine-Gwo
authors.initials: SG
authors.lastname: Shiah
authors.affiliation: Department of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Jang-Shiun
authors.initials: JS
authors.lastname: Wang
authors.affiliation: Department of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan ; Graduate Institute of Medical Sciences, Taipei Medical University, Taipei, Taiwan.
authors.forename: Wan-Wan
authors.initials: WW
authors.lastname: Lin
mesh_terms: D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D004789:Enzyme Activation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism*; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism; D051379:Mice; D010766:Phosphorylation / Q000187:drug effects; D011401:Promoter Regions, Genetic / Q000187:drug effects / Q000235:genetics; D055503:Protein Multimerization; D020836:Protein Structure, Quaternary; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics*; D015398:Signal Transduction / Q000187:drug effects; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D051996:Transcription Factor RelA / Q000737:chemistry* / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D050807:ets-Domain Protein Elk-1 / Q000378:metabolism
chemical_list: C494113:Elk1 protein, mouse; D016760:Proto-Oncogene Proteins c-fos; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; D050807:ets-Domain Protein Elk-1; D051550:I-kappa B Kinase; D048049:Extracellular Signal-Regulated MAP Kinases; D013755:Tetradecanoylphorbol Acetate