Functionally significant mutations in the Epstein-Barr virus LMP1 gene and their role in activation of cell signaling pathways
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Latent membrane protein 1 (LMP1) of the Epstein-Barr virus is a constitutively activated analog of the tumor necrosis factor receptor TNF-R1. LMP1 serves as a viral oncogen able to transform human B-ymphocytes and rodent fibroblasts via activation of numerous cellular signal cascades. Two specific motifs within LMP1 are responsible for interaction of this viral protein with the receptor protein β-TrCP/HOS SCF of the ubiquitin ligase E3 complex, playing an important role in degradation of numerous cellular proteins including NF-κB inhibitor IκBα. In this study, we demonstrate for the first time the importance of point mutations affecting HOS-recognizing motifs of LMP1 for activation of NF-κB, AP1, and PI3K/Akt signaling pathways. It has also been shown that rat fibroblast cell lines (Rat-1) expressing different HOS mutants of LMP1 produce different amounts of reactive nitrogen species. Our data confirm the hypothesis that point mutations in the C-terminal region of the LMP1 cytoplasmic domain can influence the transforming potential of the Epstein-Barr virus.
Key wordsEpstein-Barr virus LMP1 protein HOS mutations NF-κB NO
proximal C-terminal activation region of LMP1
distal C-terminal activation region of LMP1
- HOS motif
amino acid sequence recognized by HOS receptor
- HOS receptor
receptor protein β-TrCP/HOS SCF of the ubiquitin ligase E3 complex
c-Jun N-terminal kinase pathway
latent membrane protein 1
phosphatidylinositol-3-kinase signaling pathway
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