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.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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5' Flanking Region / genetics
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Antineoplastic Agents / pharmacology
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Base Sequence
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Cells, Cultured
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DNA-Binding Proteins / metabolism*
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Enzyme Induction / drug effects
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Enzyme Induction / physiology
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Gene Expression Regulation, Enzymologic / drug effects
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Humans
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Interferon-gamma / pharmacology
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Interleukin-1 / pharmacology
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Molecular Sequence Data
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Mutagenesis / physiology
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Nitric Oxide Synthase / genetics*
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Nitric Oxide Synthase / metabolism
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Nitric Oxide Synthase Type II
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Oligodeoxyribonucleotides, Antisense / pharmacology
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Promoter Regions, Genetic / physiology
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Proto-Oncogene Proteins c-fos / metabolism*
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Respiratory Mucosa / cytology
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Respiratory Mucosa / enzymology*
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STAT1 Transcription Factor
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Signal Transduction / physiology
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Trans-Activators / metabolism*
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Transcription Factor AP-1 / metabolism
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Transcriptional Activation
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Tumor Necrosis Factor-alpha / pharmacology
Substances
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Antineoplastic Agents
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DNA-Binding Proteins
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Interleukin-1
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Oligodeoxyribonucleotides, Antisense
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Proto-Oncogene Proteins c-fos
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STAT1 Transcription Factor
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STAT1 protein, human
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Trans-Activators
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Transcription Factor AP-1
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Tumor Necrosis Factor-alpha
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Interferon-gamma
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NOS2 protein, human
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Nitric Oxide Synthase
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Nitric Oxide Synthase Type II