title: Epstein-Barr virus LMP-1 natural sequence variants differ in their potential to activate cellular signaling pathways.
abstract: The latent membrane protein 1 (LMP-1) oncogene of Epstein-Barr virus (EBV) is believed to contribute to the development of many EBV-associated tumors, and there is evidence that sequence variation can affect some functions of LMP-1. Most studies have been restricted to the prototype B95.8 LMP-1 gene and genes isolated from EBV of nasopharyngeal carcinoma (NPC) patients. Here, we analyzed the signaling functions of LMP-1 from a panel of nine EBV isolates, including representatives of four defined groups of European LMP-1 variants (groups A to D [K. Sandvej, J. W. Gratama, M. Munch, X. G. Zhou, R. L. Bolhuis, B. S. Andresen, N. Gregersen, and S. Hamilton-Dutoit, Blood 90:323-330, 1997]) and Chinese NPC-derived LMP-1. Chinese and group D variants activated the transcription factor NF-kappa B two- to threefold more efficiently than B95.8 LMP-1, while Chinese, group B, and group D variants similarly activated activator protein 1 (AP-1) transcription more efficiently than did B95.8 LMP-1. However, there were no amino acid substitutions in the core binding regions for tumor necrosis factor receptor-associated adapter proteins known to mediate NF-kappa B and AP-1 activation. In contrast, despite sequence variation in the proposed Janus kinase 3 binding region, STAT activation was remarkably constant among the panel of LMP-1 variants. Analysis of the induction of CD54 (intercellular adhesion molecule 1) protein expression by the LMP-1 variants showed differences that did not correlate with either NF-kappa B or AP-1. Therefore, while the defined sequence variant groups do correlate with LMP-1 function, the results highlight the fact that the relationship between sequence variation and signaling function is extremely complex. It appears unlikely that one particular amino acid substitution or deletion will define a disease-associated variant of LMP-1.
authors.affiliation: Section of Infection and Immunity, Department of Medicine, University of Wales College of Medicine, Cardiff CF14 4XN, Wales, United Kingdom.
authors.forename: C A
authors.initials: CA
authors.lastname: Fielding
authors.forename: K
authors.initials: K
authors.lastname: Sandvej
authors.forename: A
authors.initials: A
authors.lastname: Mehl
authors.forename: P
authors.initials: P
authors.lastname: Brennan
authors.forename: M
authors.initials: M
authors.lastname: Jones
authors.forename: M
authors.initials: M
authors.lastname: Rowe
mesh_terms: D000595:Amino Acid Sequence; D014644:Genetic Variation; D004854:Herpesvirus 4, Human / Q000502:physiology*; D006801:Humans; D019169:Jurkat Cells; D008969:Molecular Sequence Data; D015398:Signal Transduction; D013329:Structure-Activity Relationship; D014763:Viral Matrix Proteins / Q000235:genetics*; D014779:Virus Replication / Q000235:genetics
chemical_list: C037662:EBV-associated membrane antigen, Epstein-Barr virus; D014763:Viral Matrix Proteins