Novel mechanisms of EBV-induced oncogenesis
Introduction
The Epstein–Barr virus is a fascinating human herpesvirus whose study has provided unique insight into host:pathogen interactions and complex cellular molecular processes. The virus is the first discovered human tumor virus and was initially identified in primary cell cultures of Burkitt lymphoma, an unusual African pediatric lymphoma [1]. The quickly developed serologic studies revealed that most people had antibodies to the virus but that patients with BL had elevated titers to specific antigenic components [2]. The serologic screenings also showed a link between elevated EBV titers and an unusual epithelial nasopharyngeal carcinoma (NPC) that developed with extraordinarily high incidence in Southern China [3]. The seroconversion of the young technician performing these early serologies following a bout with infectious mononucleosis led to definitive serologic studies that proved infectious mononucleosis was the disease manifestation associated with primary infection [4].
The continuing studies of EBV have identified additional cancers and diseases linked to EBV [5]. An overarching goal has been to define in what way a virus that is carried by almost everyone contributes to intriguing and unique cancers. The study of EBV has illuminated the molecular biology of latent herpesvirus infection and new potent mechanisms through which cell growth can be modulated by viruses. This review will summarize key findings that form the basis for our understanding of EBV pathogenesis with special emphasis on newly identified potential mechanisms through which EBV alters cellular growth.
Section snippets
EBV biology and link to human cancers
The biologic properties of the virus were immediately intriguing as it was shown that the cell lines could be established from BL samples and could produce virus that could infect primary B cells with EBV and transform them into immortalized cell lines. This powerful molecular phenotype has led to the identification of the viral proteins that are essential for latent infection and required for cell transformation [6]. Virus production can be induced in the cell lines where most of infected
EBV transformation and viral oncoproteins
Interestingly, differences in viral expression comparing EBV expression in transformed lymphocytes to that in tumor samples were identified in early studies. Comparison of sequences encoding polyadenylated RNA from Burkitt lymphoma biopsy material identified abundant transcription from specific restriction enzyme fragments that was not detected in transformed cell lines [12]. Similar studies of NPC biopsy samples indicated that the sequences later shown to encode EBNA2 and EBNA3 were not
Latent membrane protein 1
Latent membrane protein 1 (LMP1) is considered the major oncogene of EBV as it has transforming properties in cultured cell lines and is essential for B-lymphocyte transformation [5]. LMP1 transcription is also consistently detected in several of the EBV-associated cancers including post-transplant lymphoma, Hodgkin Disease (HD), and nasopharyngeal carcinoma (NPC). LMP1 functions as a constitutively active member of the tumor necrosis factor receptor family and activates multiple signaling
Latent membrane protein 2
The Epstein–Barr virus (EBV) latent membrane protein 2A (LMP2A) is important for maintenance of latency in infected B lymphocytes and also modulates epithelial cell growth [21]. Through its immunoreceptor tyrosine-based activation motif (ITAM) and PY motifs, LMP2A is able to block B cell receptor (BCR) signaling, bind BCR-associated kinases, and manipulate the turnover of itself and these kinases via a PY-mediated interaction with the Nedd4 family of ubiquitin ligases. In B cells, LMP2A
Viral miRNAs
One of the most exciting recent findings in molecular biology has been the identification of microRNAs (miRNAs) that mediate another type of regulation of cellular gene expression [26••]. miRNAs are approximately 22-nucleotide long single stranded RNAs that are closely related to small interfering RNAs (siRNAs) [26••]. It is thought that most miRNAs inhibit the translation of mRNAs by targeting an inhibitory complex to specific mRNAs based on base pair complementarity. The first viral miRNAs to
Conclusions
The molecular studies of EBV transforming proteins have shown them to be a molecular treasure treasure trove that has revealed key regulatory mechanism in critical cell pathways. The EBNA proteins have helped clarify Notch regulated signaling and the properties of the major Notch DNA binding protein, RBPJκ. LMP1 and its interactions with ubiquitin ligases have enabled dissection of NF-κB regulation and led to the identification of canonical, noncanonical, and bcl3 mediated targets. Future
References and recommended reading
Papers of particular interest, published within the period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Acknowledgement
The summarized studies have been supported by the grants from the National Cancer Institute, CA19014, CA138811, and CA32979 to NR-T
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