title: Characterization of intercellular adhesion molecule-1 regulation by Epstein-Barr virus-encoded latent membrane protein-1 identifies pathways that cooperate with nuclear factor kappa B to activate transcription.
abstract: The latent membrane protein-1 (LMP1) of Epstein-Barr virus induces gene transcription, phenotypic changes, and oncogenic transformation. One cellular gene induced by LMP1 is that for intercellular adhesion molecule-1 (ICAM-1), which participates in a wide range of inflammatory and immune responses. ICAM-1 may enhance the immune recognition of cells transformed by Epstein-Barr virus, and thus combat development of malignancy. Despite growing understanding of the various signaling functions of LMP1, the molecular mechanisms by which LMP1 induces ICAM-1 are not understood. Here, we demonstrate that transcriptional activation by LMP1 is absolutely dependent upon a variant NF-kappaB motif within the tumor necrosis factor alpha (TNFalpha) response element of the ICAM-1 promoter. Although the TNFalpha response element is sufficient for TNFalpha induction of the ICAM-1 promoter, LMP1 also required the cooperation of additional upstream sequences for optimal induction. Inhibitor studies of known LMP1-induced signaling pathways ruled out the involvement of c-Jun N-terminal kinase (JNK), p38 mitogen-activated protein kinase, and the Janus-activating tyrosine kinase 3 (JAK3), and confirmed NF-kappaB as a critical factor for induction of ICAM-1. However, although constitutive activation of NF-kappaB efficiently induced promoter activity, it was not sufficient to induce either ICAM-1 mRNA or ICAM-1 protein. Using signaling defective LMP1 mutants and deacetylation inhibitors, we showed that the C-terminal activator region 1 of LMP1 delivers a new cooperating signal to induce ICAM-1 mRNA.
authors.affiliation: Department of Medicine, Tenovus Building, University of Wales College of Medicine, Cardiff CF14 4XX, United Kingdom.
authors.forename: A M
authors.initials: AM
authors.lastname: Mehl
authors.forename: J E
authors.initials: JE
authors.lastname: Floettmann
authors.forename: M
authors.initials: M
authors.lastname: Jones
authors.forename: P
authors.initials: P
authors.lastname: Brennan
authors.forename: M
authors.initials: M
authors.lastname: Rowe
mesh_terms: D001402:B-Lymphocytes; D004268:DNA-Binding Proteins / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D017930:Genes, Reporter; D004854:Herpesvirus 4, Human / Q000235:genetics*; D006801:Humans; D020672:I-kappa B Proteins; D007093:Imidazoles / Q000494:pharmacology; D018799:Intercellular Adhesion Molecule-1 / Q000032:analysis / Q000235:genetics*; D019169:Jurkat Cells; D008156:Luciferases / Q000235:genetics; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism*; D009856:Oncogene Proteins, Viral / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011725:Pyridines / Q000494:pharmacology; D011993:Recombinant Fusion Proteins / Q000032:analysis / Q000096:biosynthesis; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014162:Transfection; D014763:Viral Matrix Proteins / Q000235:genetics* / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: D004268:DNA-Binding Proteins; C037662:EBV-associated membrane antigen, Epstein-Barr virus; D004791:Enzyme Inhibitors; D020672:I-kappa B Proteins; D007093:Imidazoles; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D009856:Oncogene Proteins, Viral; D011725:Pyridines; D011993:Recombinant Fusion Proteins; D014763:Viral Matrix Proteins; D018799:Intercellular Adhesion Molecule-1; D000072000:NF-KappaB Inhibitor alpha; D008156:Luciferases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580