Abstract
Latent membrane protein 1 (LMP1) is an Epstein-Barr virus (EBV) oncogenic protein that has no intrinsic enzymatic activity or sequence homology to cellular or viral proteins. The oncogenic potential of LMP1 has been ascribed to pleiotropic signaling properties initiated through protein-protein interactions in cytosolic membrane compartments, but the effects of LMP1 extend to nuclear and extracellular processes. Although LMP1 is one of the latent genes required for EBV-immortalization of B cells, the biology of LMP1 in the pathogenesis of the epithelial cancer nasopharyngeal carcinoma (NPC) is more complex. NPC is prevalent in specific regions of the world with high incidence in southeast China. The epidemiology and time interval from seroconversion to NPC onset in adults would suggest the involvement of multiple risk factors that complement the establishment of a latent and persistent EBV infection. The contribution of LMP1 to EBV pathogenesis in polarized epithelia has only recently begun to be elucidated. Furthermore, the LMP1 gene has emerged as one of the most divergent sequences in the EBV genome. This review will discuss the significance of recent advances in NPC research from elucidating LMP1 function in epithelial cells and lessons that could be learned from mining LMP1 sequence diversity.
Highlights
In 1964, Tony Epstein and Yvonne Barr observed herpesvirus-like particles in electron micrographs of Burkitt lymphoma cells [1]
One important distinction of latent Epstein-Barr virus (EBV) infection in all EBV-associated cancers, compared to the integrated genomes and consequential unlicensed expression of viral oncogenes associated with other human tumor viruses such as human papillomavirus (HPV), hepatitis B virus (HBV) and Merkel cell polyomavirus (MCV), is that EBV genomes are maintained in their natural infectious configuration as extrachromosomal episomes in EBV-associated cancers [75]
One of the biggest challenges in relating Latent membrane protein 1 (LMP1) research to nasopharyngeal carcinoma (NPC) pathogenesis is the limited experimental systems that tests for LMP1 biology in epithelial infection
Summary
In 1964, Tony Epstein and Yvonne Barr observed herpesvirus-like particles in electron micrographs of Burkitt lymphoma cells [1] This was the founding discovery that eventually associated a ubiquitous-herpesvirus (Epstein-Barr virus, EBV) with human cancers [2,3,4]. Despite the strong association of LMP1 expression to the immortalizing and pro-survival properties in B-lymphocytes, the molecular basis to explain how latent EBV infection can be a co-factor in the EBV-associated epithelial cancer nasopharyngeal carcinoma (NPC) has been more enigmatic [6,16]. One of the most important observations in associating EBV infection to NPC is that EBV infection is clonal in early preinvasive lesions and in the NPC tumor [21,22]. This review will focus on the latest developments on EBV epithelial infection models, discuss the implications of LMP1 sequence diversity, and summarize LMP1 effects on nuclear and extracellular processes
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