Epstein-Barr Virus Nuclear Antigen-1, Action and Reaction as an Oncogene

Abstract

The herpesvirus Epstein-Barr virus (EBV) leads to a life-long persistent infection and greater than 90% of the adult population of the world are seropositive. EBV is the causative agent of infectious mononucleosis, but in addition, the virus is associated with certain tumours of B-cell and epithelia cell origin (as well as some rare T-cell tumours). EBV nuclear antigen 1 (EBNA1) is an essential viral protein, required for the maintenance, replication and mitotic segregation of viral genome episomes. EBNA1 is a DNA binding protein and also interacts with several cellular proteins, thereby affecting host cell-signalling pathways and in so doing may contribute to cell survival and proliferation. EBNA1 is the only latent protein that is expressed in all EBV-associated malignancies and is thought to play a significant role in viral tumourigenesis. In order to explore the oncogenic mechanism of EBNA1, B-cell lymphoma samples from transgenic mice expressing EBNA1 (EµEBNA1 mice) and/or c-Myc (Eµc-Myc mice) were analysed by immunoblotting. Several candidate cellular proteins likely involved in the tumourigenic process were examined, including C-myc, Mdm2, p53, PTEN, Akt and others. Overexpression of specific MDM2 isoforms were detected in all EBNA1 tumour samples, not detected in c-Myc tumour samples, or in pre-tumour or transgene negative samples. Thus there is a specific correlation of the overexpression of Mdm2, with EBNA1-induced tumourigenesis, likely reflecting the underlying mechanism. In addition, C-Myc was overexpressed in EBNA1 tumours, supporting our previous observations regarding the cooperation of these two proteins in tumourigenesis