title: NF-kappaB activation stimulates transcription and replication of retrovirus XMRV in human B-lineage and prostate carcinoma cells.
abstract: Xenotropic murine leukemia virus-related virus (XMRV) is a gammaretrovirus linked to prostate carcinoma and chronic fatigue syndrome. Here we report that NF-κB activation can markedly increase XMRV production. The inflammatory cytokine tumor necrosis factor alpha (TNF-α), which activates NF-κB, significantly augmented viral Gag protein production in XMRV-infected cells. Reporter assays showed that TNF-α and Epstein-Barr virus (EBV) latent membrane protein 1 (LMP1), an intrinsic NF-κB activator, increased long terminal repeat (LTR)-dependent XMRV transcription. We identified two NF-κB binding sites (designated κB-1 and κB-2) in the LTR U3 region of XMRV and demonstrated that both sites bind to the NF-κB component p65/RelA. Mutation of the κB-1 site, but not the κB-2 site, impaired responsiveness to TNF-α and LMP1 in reporter assays. A mutant XMRV with a mutation at the κB-1 site replicated significantly less efficiently than the wild-type XMRV in the prostate carcinoma LNCaP, DU145, and PC-3 cell lines, HEK293 cells, the EBV-immortalized cell line IB4, and the Burkitt's lymphoma cell line BJAB. These results demonstrate that TNF-α and EBV LMP1 enhance XMRV replication in prostate carcinoma and B-lineage cells through the κB-1 site in the XMRV LTR, suggesting that inflammation, EBV infection, and other conditions leading to NF-κB activation may promote XMRV spread in humans.
authors.affiliation: Laboratory of Cellular Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Building 37, Room 4134, Bethesda, MD 20892-1907, USA. sakakibs@mail.nih.gov
authors.forename: Shuhei
authors.initials: S
authors.lastname: Sakakibara
authors.forename: Kaori
authors.initials: K
authors.lastname: Sakakibara
authors.forename: Giovanna
authors.initials: G
authors.lastname: Tosato
mesh_terms: D001402:B-Lymphocytes / Q000821:virology*; D001665:Binding Sites; D002277:Carcinoma / Q000821:virology*; D045744:Cell Line, Tumor; D015683:Gene Products, gag / Q000096:biosynthesis; D006801:Humans; D008297:Male; D016328:NF-kappa B / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000821:virology*; D011485:Protein Binding; D020079:Terminal Repeat Sequences / Q000235:genetics; D051996:Transcription Factor RelA / Q000378:metabolism; D014158:Transcription, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014779:Virus Replication; D058008:Xenotropic murine leukemia virus-related virus / Q000502:physiology*
chemical_list: D015683:Gene Products, gag; D016328:NF-kappa B; C498143:RELA protein, human; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha