title: Multiple signal transducers and activators of transcription are induced by EBV LMP-1.
abstract: Epstein-Barr virus (EBV) latent membrane protein 1 (LMP-1) is required for EBV immortalization of primary B cells in vitro. Signal transducers and activators of transcription (STATs) play a pivotal role in the initiation and maintenance of certain cancers. STAT proteins, especially STAT-1, -3, and -5, are persistently tyrosine phosphorylated or activated in many cancers. We show here that EBV-infected type III latency cells, in which the EBV oncoprotein, LMP-1 is expressed, express high levels of four STATs (STAT-1, -2, -3, and -5A) and that LMP-1 is responsible for the induction of three (STAT-1, -2, and -3). In addition, the C-terminal activator region 1 (CTAR-1) and CTAR-2 of LMP-1 cooperatively induced the expression of STAT-1. The cooperativity was evident when CTAR-1 and CTAR-2 were present in cis, but not in trans. Furthermore, NF-kappaB is an essential factor involved in the induction of STAT-1. Most of the induced STATs were not phosphorylated at the critical tyrosine residue activated by many cytokines. However, the induced STATs, at least STAT-1, were functional because it could be activated by interferon (IFN) and could upregulate an IFN-inducible gene. Finally, expression of STAT-1, but not STAT-2 and -3, is associated with EBV transformation. The association of the expression of STAT-1, -2, -3, and -5A with EBV type III latency and the expression of STAT-1 in the EBV transformation process may be part of the viral programming that regulates viral latency and cellular transformation.
authors.affiliation: Nebraska Center for Virology, School of Biological Sciences, University of Nebraska, Lincoln, NE 68588, USA. lzhang2@unlnotes.unl.edu
authors.forename: Luwen
authors.initials: L
authors.lastname: Zhang
authors.forename: Ke
authors.initials: K
authors.lastname: Hong
authors.forename: Jun
authors.initials: J
authors.lastname: Zhang
authors.forename: Joseph S
authors.initials: JS
authors.lastname: Pagano
mesh_terms: D001402:B-Lymphocytes / Q000821:virology; D002460:Cell Line; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D004854:Herpesvirus 4, Human / Q000502:physiology*; D006801:Humans; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation; D012313:RNA / Q000235:genetics / Q000378:metabolism; D050794:STAT1 Transcription Factor; D050795:STAT2 Transcription Factor; D050796:STAT3 Transcription Factor; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D014763:Viral Matrix Proteins / Q000737:chemistry / Q000378:metabolism*; D017735:Virus Latency
chemical_list: D004268:DNA-Binding Proteins; C037662:EBV-associated membrane antigen, Epstein-Barr virus; D016328:NF-kappa B; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D050795:STAT2 Transcription Factor; C494084:STAT2 protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D015534:Trans-Activators; D014763:Viral Matrix Proteins; D012313:RNA