Epstein-Barr virus-mediated B-cell proliferation is dependent upon latent membrane protein 1, which simulates an activated CD40 receptor.
The Epstein-Barr virus (EBV) latent membrane protein 1 (LMP1) is essential for the immortalization of human B cells and is linked etiologically to several human tumors. LMP1 is an integral membrane protein which acts like a constitutively active receptor. It binds tumor necrosis factor (TNF)-receptor-associated factors (TRAFs), activates NF-kappaB and triggers the transcription factor AP-1 via the c-Jun N-terminal kinase (JNK) cascade, but its specific contribution to B-cell immortalization has not been elucidated fully. To address the function of LMP1, we established B cell lines with a novel mini-EBV plasmid in which the LMP1 gene can be regulated at will without affecting the expression of other latent EBV genes. We demonstrate here that continuous expression of LMP1 is essential for the proliferation of EBV-immortalized B cells in vitro. Re-induction of LMP1 expression or activation of the cellular CD40 receptor both induce the JNK signaling cascade, activate the transcription factor NF-kappaB and stimulate proliferation of these B cells. Our findings strongly suggest that LMP1 mimics B-cell activation processes which are physiologically triggered by CD40-CD40 ligand signals. Since LMP1 acts in a ligand-independent manner, it replaces the T cell-derived activation signal to sustain indefinite B-cell proliferation.
Kilger
E
E
GSF-National Research Center for Environment and Health, Institut f¿r Klinische Molekularbiologie und Tumorgenetik, Marchioninistr. 25, D-81377 Munich, Germany.
Kieser
A
A
Baumann
M
M
Hammerschmidt
W
W
D001402:B-Lymphocytes / Q000166:cytology / Q000821:virology*; D019013:CD40 Antigens / Q000502:physiology*; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D002455:Cell Division; D002461:Cell Line, Transformed; D002472:Cell Transformation, Viral / Q000502:physiology*; D019309:Epstein-Barr Virus Nuclear Antigens / Q000032:analysis; D005786:Gene Expression Regulation / Q000187:drug effects; D005822:Genetic Vectors; D004854:Herpesvirus 4, Human / Q000502:physiology*; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D016328:NF-kappa B / Q000378:metabolism; D012097:Repressor Proteins; D015398:Signal Transduction / Q000502:physiology; D013752:Tetracycline / Q000494:pharmacology; D014763:Viral Matrix Proteins / Q000235:genetics / Q000502:physiology*
D019013:CD40 Antigens; C037662:EBV-associated membrane antigen, Epstein-Barr virus; D019309:Epstein-Barr Virus Nuclear Antigens; D016328:NF-kappa B; D012097:Repressor Proteins; D014763:Viral Matrix Proteins; C034811:tetracycline resistance-encoding transposon repressor protein; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D013752:Tetracycline