Tumor-derived variants of Epstein-Barr virus latent membrane protein 1 induce sustained Erk activation and c-Fos.
Latent membrane protein 1 (LMP1) of Epstein-Barr virus (EBV) is a proven oncogene that is essential for transformation of human B cells by the virus. LMP1 induces constitutive activation of several signal transduction pathways involving nuclear factor kappaB, phosphatidylinositol 3-kinase/Akt, and the mitogen-activated protein kinases (MAPK) p38, c-Jun N-terminal kinase (JNK), and extracellular signal-regulated kinase (Erk). Sequencing of LMP1 isolated from a panel of EBV+ B cell lymphomas identified three different variants of LMP1, each distinct from the B95.8 prototype isoform. All tumor variants of LMP1 as well as the B95.8 LMP1 isoform were able to induce rapid p38 phosphorylation as well as Akt and JNK activation. Additionally all variants showed similar ability to activate nuclear factor kappaB. In contrast, only tumor-derived LMP1 variants induced prolonged Erk activation and c-Fos expression. Sequence analysis revealed only two amino acids, 212 and 366, shared by the tumor variants but distinct from B95.8. Point mutation of either amino acids 212 (glycine to serine) or 366 (serine to threonine) from the B95.8 isoform to the tumor variant version of LMP1 was sufficient for gain of function characterized by sustained activation of Erk and subsequent c-Fos induction and binding to the AP1 site. Our results indicate that the enhanced ability of tumor-derived LMP1 to induce and stabilize the c-Fos oncogene can be localized to two amino acids in the C terminus of LMP1.
Vaysberg
Maria
M
Program in Immunology, Department of Surgery, Division of Transplantation, Stanford University School of Medicine, Stanford, California 94305, USA.
Hatton
Olivia
O
Lambert
Stacie L
SL
Snow
Andrew L
AL
Wong
Bonnie
B
Krams
Sheri M
SM
Martinez
Olivia M
OM
D000595:Amino Acid Sequence; D045744:Cell Line, Tumor; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic; D015967:Gene Expression Regulation, Viral; D006801:Humans; D008969:Molecular Sequence Data; D009369:Neoplasms / Q000378:metabolism* / Q000821:virology; D017354:Point Mutation; D017434:Protein Structure, Tertiary; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014763:Viral Matrix Proteins / Q000378:metabolism*
C037662:EBV-associated membrane antigen, Epstein-Barr virus; D016760:Proto-Oncogene Proteins c-fos; D018808:Transcription Factor AP-1; D014763:Viral Matrix Proteins; D048049:Extracellular Signal-Regulated MAP Kinases