Oncogenic activity of Epstein-Barr virus latent membrane protein 1 (LMP-1) is down-regulated by lytic LMP-1.
The Epstein-Barr virus (EBV) is an oncogenic human herpesvirus. EBV latent membrane protein 1 (LMP-1) is a viral oncogene that manifests its oncogenic phenotype through activation of cellular signaling pathways involved in cell growth, survival, differentiation, and transformation. Lytic LMP-1 (lyLMP-1) is a related EBV gene without oncogenic properties. The lyLMP-1 gene is found in 60% of the EBV strains circulating in nature, but it is not found in EBV strains associated with nasopharyngeal carcinoma. We recently demonstrated that lyLMP-1 down-regulates the half-life of LMP-1 in epithelial cells. Therefore in this study, we tested the hypothesis that lyLMP-1 concomitantly down-regulates LMP-1 oncogenic activity. The results demonstrated that lyLMP-1 inhibits LMP-1-mediated intracellular signaling activation, epithelial cell growth and survival, and fibroblast cell transformation in a dose-dependent manner. Lytic LMP-1 manifested this effect through the promotion of LMP-1 degradation and a reduction in the expressed quantity of LMP-1. Thus, lyLMP-1 functions as a posttranslational negative regulator of LMP-1 oncogenesis. These results support a model of EBV-associated epithelial oncogenesis in which lyLMP-1 may act in vivo to reduce the risk of LMP-1-mediated transformation and is therefore subjected to negative selection in nasopharyngeal carcinoma pathogenesis.
Pandya
Jyotsna
J
Division of Infectious Diseases, Department of Internal Medicine, University of Texas Medical Branch, 301 University Boulevard, Galveston, Texas 77555-0435, USA.
Walling
Dennis M
DM
D000818:Animals; D002277:Carcinoma / Q000821:virology*; D002472:Cell Transformation, Viral; D015536:Down-Regulation; D004854:Herpesvirus 4, Human / Q000502:physiology*; D006801:Humans; D051379:Mice; D009303:Nasopharyngeal Neoplasms / Q000821:virology*; D011401:Promoter Regions, Genetic; D014763:Viral Matrix Proteins / Q000378:metabolism*; D014775:Virus Activation; D017735:Virus Latency
C037662:EBV-associated membrane antigen, Epstein-Barr virus; D014763:Viral Matrix Proteins