title: The Epstein-Barr virus replication and transcription activator, Rta/BRLF1, induces cellular senescence in epithelial cells.
abstract: Epstein-Barr Virus (EBV) replication and transcription activator (Rta/BRLF1) is an immediate-early transcription factor that controls the conversion of the latent viral genome into one undergoing lytic replication. By using a doxycycline-inducible expression system, the present study demonstrates that EBV Rta efficiently elicits growth arrest in the human epithelial cell line HEK293. In cells arrested by EBV Rta, the expression of p21 (CDKN1A), p27 (CDKN1B) and cyclin E were increased. In contrast, the levels of cyclin D1, CDK4 and CDK6 were sharply decreased. Activation of the host cell DNA damage response (DDR), indicated by the increasing phosphorylation of H2AX and p53 Ser15, was observed on day 3 and day 5 after EBV Rta expression, respectively. Finally, EBV Rta arrested cells exhibited strong senescence-associated beta-galactosidase staining on day 10 after doxycycline induction. Together, these results indicate that, in addition to triggering viral lytic replication in epithelial cells, EBV Rta concurrently initiates a cellular senescence program that was previously undocumented. This finding, showing Rta may be centrally involved in inducing a host cell state amenable to efficient viral reproduction, in addition to its previously characterized regulation of viral transcription, provides new perspectives in understanding EBV pathogenesis.
authors.affiliation: National Institute of Cancer Research, National Health Research Institutes, No. 35 Keyan Road, Zhunan Town, Miaoli County, Taiwan.
authors.forename: Yu-Lian
authors.initials: YL
authors.lastname: Chen
authors.forename: Yen-Ju
authors.initials: YJ
authors.lastname: Chen
authors.forename: Wan-Hua
authors.initials: WH
authors.lastname: Tsai
authors.forename: Ying-Chieh
authors.initials: YC
authors.lastname: Ko
authors.forename: Jen-Yang
authors.initials: JY
authors.lastname: Chen
authors.forename: Su-Fang
authors.initials: SF
authors.lastname: Lin
mesh_terms: D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D016922:Cellular Senescence / Q000187:drug effects; D004318:Doxycycline / Q000494:pharmacology; D004847:Epithelial Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D016193:G1 Phase / Q000187:drug effects; D004854:Herpesvirus 4, Human / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D017874:Immediate-Early Proteins / Q000378:metabolism*; D007700:Kinetics; D008156:Luciferases / Q000378:metabolism; D009305:Nasopharynx / Q000166:cytology; D055550:Protein Stability / Q000187:drug effects; D013752:Tetracycline / Q000494:pharmacology; D015534:Trans-Activators / Q000378:metabolism*; D014779:Virus Replication / Q000187:drug effects / Q000502:physiology*; D001616:beta-Galactosidase / Q000378:metabolism
chemical_list: C068382:BRLF1 protein, Human herpesvirus 4; D017874:Immediate-Early Proteins; D015534:Trans-Activators; D008156:Luciferases; D001616:beta-Galactosidase; D013752:Tetracycline; D004318:Doxycycline