Epstein-Barr virus latent membrane protein-1 triggers AP-1 activity via the c-Jun N-terminal kinase cascade.
The Epstein-Barr virus latent membrane protein-1 (LMP-1) is an integral membrane protein which transforms fibroblasts and is essential for EBV-mediated B-cell immortalization. LMP-1 has been shown to trigger cellular NF-kappa B activity which, however, cannot fully explain the oncogenic potential of LMP-1. Here we show that LMP-1 induces the activity of the AP-1 transcription factor, a dimer of Jun/Jun or Jun/Fos proteins. LMP-1 effects on AP-1 are mediated through activation of the c-Jun N-terminal kinase (JNK) cascade, but not the extracellular signal-regulated kinase (Erk) pathway. Consequently, LMP-1 triggers the activity of the c-Jun N-terminal transactivation domain which is known to be activated upon JNK-mediated phosphorylation. Deletion analysis indicates that the 55 C-terminal amino acids of the LMP-1 molecule, but not its TRAF interaction domain, are essential for AP-1 activation. JNK-mediated transcriptional activation of AP-1 is the direct output of LMP-1-triggered signaling, as shown by an inducible LMP-1 mutant. Using a tetracycline-regulated LMP-1 allele, we demonstrate that JNK is also an effector of non-cytotoxic LMP-1 signaling in B cells, the physiological target cells of EBV. In summary, our data reveal a novel effector of LMP-1, the SEK/JNK/c-Jun/AP-1 pathway, which contributes to our understanding of the immortalizing and transforming potential of LMP-1.
Kieser
A
A
GSF-National Research Center for Environment and Health, Institute for Clinical Molecular Biology and Tumor Genetics, München, Germany.
Kilger
E
E
Gires
O
O
Ueffing
M
M
Kolch
W
W
Hammerschmidt
W
W
D001402:B-Lymphocytes / Q000378:metabolism; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000032:analysis / Q000502:physiology*; D002472:Cell Transformation, Viral / Q000502:physiology; D002478:Cells, Cultured; D015967:Gene Expression Regulation, Viral; D004854:Herpesvirus 4, Human / Q000235:genetics / Q000502:physiology*; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases; D007668:Kidney; D048670:MAP Kinase Kinase 4; D019950:Mitogen-Activated Protein Kinase 1; D020929:Mitogen-Activated Protein Kinase Kinases; D020928:Mitogen-Activated Protein Kinases; D011494:Protein Kinases / Q000235:genetics / Q000502:physiology; D016755:Proto-Oncogene Proteins c-jun / Q000737:chemistry; D015398:Signal Transduction / Q000502:physiology*; D018808:Transcription Factor AP-1 / Q000737:chemistry / Q000378:metabolism*; D015533:Transcriptional Activation; D014763:Viral Matrix Proteins / Q000502:physiology*
C037662:EBV-associated membrane antigen, Epstein-Barr virus; D016755:Proto-Oncogene Proteins c-jun; D018808:Transcription Factor AP-1; D014763:Viral Matrix Proteins; D011494:Protein Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D020928:Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; C482559:MAP2K4 protein, human; D020929:Mitogen-Activated Protein Kinase Kinases