title: Epstein-Barr virus-encoded Bcl-2 homologue functions as a survival factor in Wp-restricted Burkitt lymphoma cell line P3HR-1.
abstract: Burkitt lymphoma (BL) is etiologically associated with Epstein-Barr virus (EBV). EBV-positive BL tumors display two latent forms of infection. One is referred to as latency I infection, in which EBV expresses the virus genome maintenance protein EBNA1 as the only viral protein. The other is referred to as Wp-restricted latency and was recently identified in a subset of BL tumors. In these tumors, EBV expresses EBNA1, EBNA3A, EBNA3B, EBNA3C, a truncated form of EBNA-LP, and the viral Bcl-2 homologue BHRF1, all of which are driven by the BamHI W promoter (Wp). To investigate the role of EBV in Wp-restricted BL, we conditionally expressed a dominant-negative EBNA1 (dnEBNA1) mutant which interrupts the virus genome maintenance function of EBNA1 in the P3HR-1 BL cell line. Induction of dnEBNA1 expression caused loss of the EBV genome and resulted in apoptosis of P3HR-1 cells in the absence of exogenous apoptosis inducers, indicating that P3HR-1 cells cannot survive without EBV. Stable transfection of the BHRF1 gene into P3HR-1 cells rescued the cells from the apoptosis induced by dnEBNA1 expression, whereas stable transfection of truncated EBNA-LP, EBNA3A, or EBNA3C did not. Moreover, knockdown of BHRF1 expression in P3HR-1 cells resulted in increased cell death. These results indicate that EBV is essential for the survival of P3HR-1 cells and that BHRF1 functions as a survival factor. Our finding implies a critical contribution of BHRF1 to the pathogenesis of Wp-restricted BLs.
authors.affiliation: Department of Tumor Virology, Institute for Genetic Medicine, Hokkaido University, N15W7, Kita-ku, Sapporo 060-0815, Japan.
authors.forename: Ami
authors.initials: A
authors.lastname: Watanabe
authors.forename: Seiji
authors.initials: S
authors.lastname: Maruo
authors.forename: Taku
authors.initials: T
authors.lastname: Ito
authors.forename: Miho
authors.initials: M
authors.lastname: Ito
authors.forename: Koichi Ricardo
authors.initials: KR
authors.lastname: Katsumura
authors.forename: Kenzo
authors.initials: K
authors.lastname: Takada
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D002051:Burkitt Lymphoma / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000502:physiology*; D020031:Epstein-Barr Virus Infections / Q000235:genetics / Q000378:metabolism; D019309:Epstein-Barr Virus Nuclear Antigens / Q000235:genetics / Q000378:metabolism; D016679:Genome, Viral; D004854:Herpesvirus 4, Human / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism*; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism*; D017735:Virus Latency / Q000235:genetics
chemical_list: C083278:BHRF1 protein, Human herpesvirus 4; D019309:Epstein-Barr Virus Nuclear Antigens; D020033:Protein Isoforms; D019253:Proto-Oncogene Proteins c-bcl-2; D014764:Viral Proteins; C417029:EBV-encoded nuclear antigen 1