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Analysis of signaling by two oncoproteins of Epstein-Barr Virus

Analysis of signaling by two oncoproteins of Epstein-Barr Virus

Lee, Jisook; Sugden, Bill. The University of Wisconsin - Madison, 2008. 2008. 3327777.

Abstract (summary)

Epstein-Barr Virus (EBV) is a gamma herpes virus that causes infectious mononucleosis and contributes to many different types of cancers. In all EBV-associated malignancies, the EBV genome is maintained as a plasmid in their proliferating cells. Signaling from two viral proteins, Latent Membrane Protein 1 (LMP1) and Epstein-Barr Nuclear Antigen 1 (EBNA1), contribute to EBV-associated malignancies either by maintaining proliferation of EBV-infected cells or by replicating and maintaining the viral genome.

LMP1 activates several signaling pathways including NF-κB, AP1 and JAK-STAT, and genetic studies indicate that signaling from LMP1 is essential for maintaining B-cell proliferation in culture. Signaling by LMP1 is regulated by its expression levels, oligomerization and targeting to lipid rafts. All of these properties are mediated through the six transmembrane domains of LMP1. I have found that a membrane leucine heptad in the first membrane-spanning domain of LMP1 is important for its proper trafficking to lipid rafts. Mutation in this leucine heptad results in defects in trafficking, signaling and transformation by LMP1.

Another essential protein found in all EBV-associated malignancies, EBNA1, binds site-specifically to DNA in order to function. EBNA1 is required for the initiation of DNA synthesis site-specifically and partitioning of the viral genome in proliferating cells. EBNA1 also activates transcription from several viral promoters, including its own, allowing viral genes important for EBV's transforming ability to be expressed. A genetic analysis of EBNA1 identified 25 amino acids with its amino-terminus (UR1) to be important for EBNA1-mediated transcription. I have found a novel interaction partner of EBNA1, ProMyelocytic Leukaemia protein (PML), which binds to UR1. The importance of this interaction is yet to be solved.

Because of their pivotal role in the tumorigenesis of EBV, both LMP1 and EBNA1 are promising targets to inhibit the role of EBV in EBV-associated malignancies. Further investigation that focuses either on the trafficking and signaling from LMP1 or the mechanism by which EBNA1 activates transcription will be useful for developing

keyword Health and environmental sciences, Epstein-Barr virus, Epstein-Barr nuclear antigen 1, Latent membrane protein 1, Oncoproteins