title: STAT-1 and c-Fos interaction in nitric oxide synthase-2 gene activation.
abstract: Interferon-gamma (IFN-gamma) is required for induction of the human nitric oxide synthase-2 (NOS2) gene in lung epithelium. Although the human NOS2 promoter region contains many cytokine-responsive elements, the molecular basis of induction is only partially understood. Here, the major cis-regulatory elements that control IFN-gamma-inducible NOS2 gene transcription in human lung epithelial cells are identified as composite response elements that bind signal transducer and activator of transcription 1 (STAT-1) and activator protein 1 (AP-1), which is comprised of c-Fos, Fra-2, c-Jun, and JunD. Notably, IFN-gamma activation of the human NOS2 promoter is shown to require functional AP-1 regulatory region(s), suggesting a role for AP-1 activation/binding in the IFN-gamma induction of genes. We show that c-Fos interacts with STAT-1 after IFN-gamma activation and the c-Fos/STAT-1 complex binds to the gamma-activated site (GAS) element in close proximity to AP-1 sites located at 4.9 kb upstream of the transcription start site. Taken together, our findings support a model in which a physical interaction between c-Fos and STAT-1 participates in NOS2 gene transcriptional activation.
authors.affiliation: Pulmonary and Critical Care Medicine and Cancer Biology, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA.
authors.forename: Weiling
authors.initials: W
authors.lastname: Xu
authors.forename: Suzy A A
authors.initials: SA
authors.lastname: Comhair
authors.forename: Shuo
authors.initials: S
authors.lastname: Zheng
authors.forename: Shan C
authors.initials: SC
authors.lastname: Chu
authors.forename: Joanna
authors.initials: J
authors.lastname: Marks-Konczalik
authors.forename: Joel
authors.initials: J
authors.lastname: Moss
authors.forename: S Jaharul
authors.initials: SJ
authors.lastname: Haque
authors.forename: Serpil C
authors.initials: SC
authors.lastname: Erzurum
mesh_terms: D024506:5' Flanking Region / Q000235:genetics; D000970:Antineoplastic Agents / Q000494:pharmacology; D001483:Base Sequence; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004790:Enzyme Induction / Q000187:drug effects / Q000502:physiology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology; D007375:Interleukin-1 / Q000494:pharmacology; D008969:Molecular Sequence Data; D016296:Mutagenesis / Q000502:physiology; D019001:Nitric Oxide Synthase / Q000235:genetics* / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D020319:Oligodeoxyribonucleotides, Antisense / Q000494:pharmacology; D011401:Promoter Regions, Genetic / Q000502:physiology; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism*; D020545:Respiratory Mucosa / Q000166:cytology / Q000201:enzymology*; D050794:STAT1 Transcription Factor; D015398:Signal Transduction / Q000502:physiology; D015534:Trans-Activators / Q000378:metabolism*; D018808:Transcription Factor AP-1 / Q000378:metabolism; D015533:Transcriptional Activation; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D007375:Interleukin-1; D020319:Oligodeoxyribonucleotides, Antisense; D016760:Proto-Oncogene Proteins c-fos; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D015534:Trans-Activators; D018808:Transcription Factor AP-1; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; C496319:NOS2 protein, human; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II