Direct and indirect regulation of cytokine and cell cycle proteins by EBNA-2 during Epstein-Barr virus infection

L C Spender, G H Cornish, B Rowland, B Kempkes, P J Farrell (Lead / Corresponding author)

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    49 Citations (Scopus)


    We have studied the pathways of regulation of cytokine and cell cycle control proteins during infection of human B lymphocytes by Epstein-Barr virus (EBV). Among 30 cytokine RNAs analyzed by the RNase protection assay, tumor necrosis factor alpha (TNF-alpha), granulocyte colony-stimulating factor, lymphotoxin (LT), and LTbeta were found to be regulated within 20 h of EBV infection of primary B cells. Similar results were obtained using the estrogen-regulated EBNA-2 cell line EREB2.5, in which RNAs for LT and TNF-alpha were induced within 6 h of activation of EBNA-2. Expression of Notch also caused an induction of TNF-alpha RNA. The induction of TNF-alpha RNA by EBNA-2 was indirect, and constitutive expression of either LMP-1 or c-myc proteins did not substitute for EBNA-2 in induction of TNF-alpha RNA. Cyclin D2 is also an indirect target of EBNA-2-mediated transactivation. EBNA-2 was found to activate the cyclin D2 promoter in a transient-transfection assay. A mutant of EBNA-2 that does not bind RBP-Jkappa retained some activity in this assay, and activation did not depend on the presence of B-cell-specific factors. Deletion analysis of the cyclin D2 promoter revealed that removal of sequences containing E-box c-myc consensus DNA binding sequences did not reduce EBNA-2-mediated activation of the cyclin D2 promoter in the transient-transfection assay. The results indicate that cytokines are an early target of EBNA-2 and that EBNA-2 can regulate cyclin D2 transcription in EBV-infected cells by mechanisms additional to the c-myc pathway.

    Original languageEnglish
    Pages (from-to)3537-3546
    Number of pages10
    JournalJournal of Virology
    Issue number8
    Publication statusPublished - Apr 2001


    • Adaptor Proteins, Signal Transducing
    • Anisomycin
    • B-Lymphocytes
    • Carrier Proteins
    • Cell Cycle Proteins
    • Cells, Cultured
    • Cyclin D2
    • Cyclin-Dependent Kinase Inhibitor p27
    • Cyclins
    • Cycloheximide
    • Cytokines
    • Cytoskeletal Proteins
    • Epstein-Barr Virus Nuclear Antigens
    • Estrogens
    • Fluorescent Antibody Technique
    • Gene Expression Regulation
    • Granulocyte Colony-Stimulating Factor
    • Herpesvirus 4, Human
    • Humans
    • Intracellular Signaling Peptides and Proteins
    • LIM Domain Proteins
    • Lymphotoxin-alpha
    • Membrane Proteins
    • Microtubule-Associated Proteins
    • Mutation
    • Nuclease Protection Assays
    • Promoter Regions, Genetic
    • Proto-Oncogene Proteins c-myc
    • RNA, Messenger
    • Receptors, Notch
    • Transcription, Genetic
    • Tumor Cells, Cultured
    • Tumor Necrosis Factor-alpha
    • Tumor Suppressor Proteins
    • Viral Proteins
    • Journal Article


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