Functionally significant mutations in the Epstein-Barr virus LMP1 gene and their role in activation of cell signaling pathways.
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 oncogene able to transform human B-lymphocytes 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 beta-TrCP/HOS SCF of the ubiquitin ligase E3 complex, playing an important role in degradation of numerous cellular proteins including NF-kappaB inhibitor IkappaBalpha. In this study, we demonstrate for the first time the importance of point mutations affecting HOS-recognizing motifs of LMP1 for activation of NF-kappaB, 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.
Diduk
S V
SV
Blokhin Cancer Research Center, Russian Academy of Medical Sciences, Moscow, 115478, Russia.
Smirnova
K V
KV
Pavlish
O A
OA
Gurtsevitch
V E
VE
D020816:Amino Acid Motifs; D000818:Animals; D002461:Cell Line, Transformed; D002478:Cells, Cultured; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D009154:Mutation; D016328:NF-kappa B / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction / Q000235:genetics*; D014763:Viral Matrix Proteins / Q000235:genetics* / Q000378:metabolism*; D044844:beta-Transducin Repeat-Containing Proteins / Q000235:genetics / Q000378:metabolism
C037662:EBV-associated membrane antigen, Epstein-Barr virus; D016328:NF-kappa B; D014763:Viral Matrix Proteins; D044844:beta-Transducin Repeat-Containing Proteins; D009569:Nitric Oxide; D019869:Phosphatidylinositol 3-Kinases