title: EBV infection induces expression of the transcription factors ATF-2/c-Jun in B lymphocytes but not in B-CLL cells.
abstract: B cell type chronic lymphocytic leukaemia (B-CLL) cells carry the Epstein-Barr virus (EBV) receptor CD21 and can be infected in vitro with the virus. The infected cells exhibit an unusual EBV program, they express the nuclear proteins but not latent membrane protein 1 (LMP-1). Similar cells were encountered in lymphoid tissues of infectious mononucleosis (IM) patients and in lymphoproliferations of immunosuppressed patients. EBV infected B-CLL cells can be regarded as model for this viral program. In B cells the regulation of LMP-1 is executed mainly by EBV encoded nuclear antigen 2 (EBNA-2), interacting with several cellular proteins and these complexes bind to specific sequences in the LMP-1 promoter. ATF2 and c-Jun were shown to be among the interacting partners of EBNA-2. These molecules can be detected in experimentally infected B lymphocytes. We found c-Jun and/or phosphorylated ATF-2 (p-ATF-2) expression in some B-CLL ex vivo samples. They disappeared or their expression declined promptly in explanted cells, even if they were infected with EBV in vitro. Activation of the infected B-CLL cells by exposure to CD40L was accompanied by p-ATF-2 and c-Jun but not by LMP-1 expression. In one of three clones tested, subsequent treatment with histone deacetylase inhibitors (HDACi), TSA or n-butyrate, could induce LMP-1. Treatment with phorbol-12, 13-dibutyrate (PDB) induced LMP-1 expression in three of four clones. Neither the HDACi nor the PDB treated cells survived.
authors.affiliation: Microbiology and Tumor Biology Center, Karolinska Institute, S-171 77, Stockholm, Sweden.
authors.forename: Kentaro
authors.initials: K
authors.lastname: Bandobashi
authors.forename: Anquan
authors.initials: A
authors.lastname: Liu
authors.forename: Noémi
authors.initials: N
authors.lastname: Nagy
authors.forename: Loránd L
authors.initials: LL
authors.lastname: Kis
authors.forename: Jun
authors.initials: J
authors.lastname: Nishikawa
authors.forename: Magnus
authors.initials: M
authors.lastname: Björkholm
authors.forename: George
authors.initials: G
authors.lastname: Klein
authors.forename: Eva
authors.initials: E
authors.lastname: Klein
mesh_terms: D051698:Activating Transcription Factor 2; D001402:B-Lymphocytes / Q000378:metabolism / Q000821:virology*; D023201:CD40 Ligand / Q000494:pharmacology; D045744:Cell Line, Tumor; D017362:Cyclic AMP Response Element-Binding Protein / Q000096:biosynthesis*; D005786:Gene Expression Regulation; D004854:Herpesvirus 4, Human / Q000235:genetics / Q000502:physiology*; D006801:Humans; D015151:Immunoblotting; D015451:Leukemia, Lymphocytic, Chronic, B-Cell; D015240:Phorbol 12,13-Dibutyrate / Q000494:pharmacology; D016755:Proto-Oncogene Proteins c-jun / Q000096:biosynthesis*; D014157:Transcription Factors / Q000096:biosynthesis*; D014763:Viral Matrix Proteins / Q000096:biosynthesis
chemical_list: C497105:ATF2 protein, human; D051698:Activating Transcription Factor 2; D017362:Cyclic AMP Response Element-Binding Protein; C037662:EBV-associated membrane antigen, Epstein-Barr virus; D016755:Proto-Oncogene Proteins c-jun; D014157:Transcription Factors; D014763:Viral Matrix Proteins; D023201:CD40 Ligand; D015240:Phorbol 12,13-Dibutyrate