Regulatory elements and transcription factors controlling basal and cytokine-induced expression of the gene encoding intercellular adhesion molecule 1.
The gene encoding intercellular adhesion molecule 1 (ICAM-1) is transcriptionally induced in response to inflammatory and immunomodulatory cytokines. To investigate the mechanisms controlling ICAM-1 gene expression, we have identified regulatory DNA sequences responsible for maintaining basal and mediating induced transcription in response to tumor necrosis factor alpha (TNF-alpha) and interferon gamma (IFN-gamma). Regulatory elements centered 115, 60, and 40 bp upstream from the ICAM-1 transcription start site were implicated in cytokine-independent gene expression. Regulatory elements dedicated to TNF-alpha and IFN-gamma were identified 190 and 90 bp, respectively, upstream from the ICAM-1 transcription start site. A combination of mutagenesis and DNA-binding assays revealed that the TNF-alpha response element is composite, consisting of binding sites for both C/EBP and NF-kappa B. The IFN-gamma response element behaved as a simple regulatory element that selectively binds to an IFN-gamma-inducible activity composed, at least in part, of p91. These observations provide a framework for understanding how extracellular signals dynamically regulate the adhesive properties of mammalian cells.
Tularik, Inc. South San Francisco, CA 94080.
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Hou
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Baichwal
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Cao
D001483:Base Sequence; D016207:Cytokines / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D066298:In Vitro Techniques; D007249:Inflammation / Q000503:physiopathology; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics*; D007371:Interferon-gamma / Q000494:pharmacology; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000378:metabolism; D009838:Oligodeoxyribonucleotides / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D012045:Regulatory Sequences, Nucleic Acid; D014157:Transcription Factors / Q000502:physiology*; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D016207:Cytokines; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D009838:Oligodeoxyribonucleotides; D012333:RNA, Messenger; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D018799:Intercellular Adhesion Molecule-1; D007371:Interferon-gamma