title: Epstein-Barr virus BZLF1 gene is activated by transforming growth factor-beta through cooperativity of Smads and c-Jun/c-Fos proteins.
abstract: Induction of Epstein-Barr virus (EBV) production in an EBV-positive cell is achieved by expression of the gene BZLF1 that switches the latent state into a lytic state. The expression of the BZLF1 gene is initiated from the promoter Zp, which is normally suppressed in EBV-transformed B cells. The BZLF1 gene can be induced for expression by activating agents, such as transforming growth factor-beta (TGF-beta) and 12-O-tetradecanoylphorbol-13-acetate. The 12-O-tetradecanoylphorbol-13-acetate-responsive element located in the Zp is the AP-1 motif. The TGF-beta-responsive element, however, has not been determined. We demonstrated that the Smad4-binding element site, GTCTG, from -233 to -229, was located in the regulatory region of the Zp relative to the BZLF1 transcription initiation site and was physically associated with Smad4. This association was important for the TGF-beta induction of Zp. We also showed from the results of co-transfection experiments and electrophoretic mobility shift assays that both the AP-1 motif and Smad4-binding element site appeared to be required for the TGF-beta-induced activation of Zp. This effect was mediated through the cooperation of Smad3/Smad4 and c-Jun/c-Fos that formed a complex. TGF-beta treatment of Rael cells induced production of infectious EBV particles that was capable of infecting EBV-negative CA46 cells and transforming normal cord blood B cells, in vitro. Those data support a mechanism that TGF-beta induces the latent EBV in cells to enter the viral lytic cycle through regulation of key viral proteins by TGF-beta signal transducers. Those findings also suggest a role of TGF-beta in EBV-associated diseases.
authors.affiliation: Institute of Microbiology and Immunology, National Yang-Ming University, Shih-Pai 112, Taipei, Republic of China.
authors.forename: Chih-Lung
authors.initials: CL
authors.lastname: Liang
authors.forename: Jo-Lin
authors.initials: JL
authors.lastname: Chen
authors.forename: Yun-Pung Paul
authors.initials: YP
authors.lastname: Hsu
authors.forename: Jonathan T
authors.initials: JT
authors.lastname: Ou
authors.forename: Yu-Sun
authors.initials: YS
authors.lastname: Chang
mesh_terms: D001483:Base Sequence; D001665:Binding Sites; D002460:Cell Line; D004279:DNA, Viral / Q000032:analysis; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000502:physiology*; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D020935:MAP Kinase Signaling System; D008969:Molecular Sequence Data; D020320:Oligoribonucleotides, Antisense / Q000494:pharmacology; D011401:Promoter Regions, Genetic; D016760:Proto-Oncogene Proteins c-fos / Q000502:physiology*; D016755:Proto-Oncogene Proteins c-jun / Q000502:physiology*; D051901:Smad4 Protein; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D015534:Trans-Activators / Q000235:genetics* / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D014764:Viral Proteins
chemical_list: C063676:BZLF1 protein, Herpesvirus 4, Human; D004279:DNA, Viral; D004268:DNA-Binding Proteins; D020320:Oligoribonucleotides, Antisense; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; C497796:SMAD4 protein, human; D051901:Smad4 Protein; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D014764:Viral Proteins; D013755:Tetradecanoylphorbol Acetate