Regulation of Survivin and CDK4 by Epstein-Barr virus encoded latent membrane protein 1 in nasopharyngeal carcinoma cell lines

Abstract

Latent membrane protein 1 (LMP1), an important protein encoded by Epstein Barr virus (EBV), has been implied to link with the pathogenesis of nasopharyngeal carcinoma (NPC). Its dual effects of increasing cell proliferation and inhibiting cell apoptosis have been confirmed. In this study, we showed that the expression of Survivin and CDK4 protein in CNE-LMP1, a LMP1 positive NPC epithelial cell line, is higher than in LMP1 negative NPC epithelial cell line-CNE1, and the expression is LMP1 dosage-dependent. Although it was reported that Survivin specifically expressed in cell cycle G 2 /M phase, our studies suggested that LMP1 could promote the expression of Survivin in G 0 /G 1 , S and G 2 / M phase. It also showed that Survivin and CDK4 could be accumulated more in the nuclei triggered by LMP1. More interestingly, Survivin and CDK4 could form a protein complex in the nuclei of CNE-LMP1 rather than in that of CNE1, which demonstrated that the interaction between these two proteins could be promoted by LMP1. These results strongly suggested that the role of LMP1 in the regulation of Survivin and CDK4 may also shed some light on the mechanism research of LMP1 in NPC.

P16 reactivation induces anoikis and exhibits antitumour potency by downregulating Akt/survivin signalling in hepatocellular carcinoma cells

“…Cyclin D1 and P16 eventually influence the G 1 –S checkpoint by interacting with CDK4 29. By co-immunoprecipitation, western blot using the nuclear and cytoplasmic extracts and immunolabelling confocal assays, we found that CDK4 was co-immunoprecipitated with survivin in P16-deficient HCC cells, both co-localised mainly in cancer cell nuclei.…”

Functional interaction of Ugene and EBV infection mediates tumorigenic effects

“…LMP1 protein is a ligand-independent tumor necrosis factor receptor, which can activate many mammalian signal transduction pathways mediated by three activation regions, 1, 2 and 3 (CTAR1, CTAR2 and CTAR3), in the C-terminal (Pai and Khanna, 2001;Kieser, 2008;Munz and Moormann, 2008). Among them, CTAR1 domain has a critical role in LMP1-induced tumor transformation and accelerates G1/S transition in NPC cells through activation of nuclear factor-kB and mitogen-activated protein kinase signaling and upregulated expression of cell cycle regulators, such as CDK4, cyclin D1, E2F1 and survivin (Tsao et al, 2002;Ai et al, 2005;Soni et al, 2007;Zheng et al, 2007;Demetriades and Mosialos, 2009), although the detailed mechanisms remain elusive. In this study, we found that LMPIP was one of the important mediators of LMP1 leading to decreased cellular ROS generation and shortened G1/S phase transition through the mitogen-activated protein kinase (extracellular signal-regulated kinase 1/2) and nuclear factor-kB signaling pathways.…”

Role of The Epstein–Barr Virus-Encoded Latent Membrane Protein-1, LMP1, in The Pathogenesis of Nasopharyngeal Carcinoma

“…Concurrent with these findings, LMP1 was independently shown to enhance the expression of survivin (BIRC5) and Cdk4 in CNE cells in a dose-dependent fashion, whilst also inducing their interaction in the nucleus [66]. LMP1 was also found to downregulate the expression of the retinoic acid receptor b2 (RARb2) in NPC cells via upregulation of DNA methyl transferases (DNMTs) 1, 3a and 3b, resulting in RARb2 promoter hypermethylation [67].…”