The c-Jun N-terminal kinase pathway is critical for cell transformation by the latent membrane protein 1 of Epstein-Barr virus.
The latent membrane protein 1 (LMP1) of Epstein-Barr virus (EBV) transforms cells activating signal transduction pathways such as NF-kappaB, PI3-kinase, or c-Jun N-terminal kinase (JNK). Here, we investigated the functional role of the LMP1-induced JNK pathway in cell transformation. Expression of a novel dominant-negative JNK1 allele caused a block of proliferation in LMP1-transformed Rat1 fibroblasts. The JNK-specific inhibitor SP600125 reproduced this effect in Rat1-LMP1 cells and efficiently interfered with proliferation of EBV-transformed lymphoblastoid cells (LCLs). Inhibition of the LMP1-induced JNK pathway in LCLs caused the downregulation of c-Jun and Cdc2, the essential G2/M cell cycle kinase, which was accompanied by a cell cycle arrest of LCLs at G2/M phase transition. Moreover, SP600125 retarded tumor growth of LCLs in a xenograft model in SCID mice. Our data support a critical role of the LMP1-induced JNK pathway for proliferation of LMP1-transformed cells and characterize JNK as a potential target for intervention against EBV-induced malignancies.
Kutz
Helmut
H
GSF-National Research Center for Environment and Health, Department of Gene Vectors, Marchioninistrasse 25, D-81377 Munich, Germany.
Reisbach
Gilbert
G
Schultheiss
Ute
U
Kieser
Arnd
A
D000818:Animals; D000873:Anthracenes / Q000494:pharmacology; D001402:B-Lymphocytes / Q000821:virology; D002460:Cell Line; D002461:Cell Line, Transformed; D002472:Cell Transformation, Viral; D020031:Epstein-Barr Virus Infections / Q000473:pathology; D005347:Fibroblasts / Q000821:virology; D004854:Herpesvirus 4, Human / Q000378:metabolism / Q000472:pathogenicity*; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008232:Lymphoproliferative Disorders / Q000473:pathology; D051379:Mice; D016513:Mice, SCID; D048055:Mitogen-Activated Protein Kinase 8 / Q000037:antagonists & inhibitors / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction; D014763:Viral Matrix Proteins / Q000378:metabolism*
D000873:Anthracenes; C037662:EBV-associated membrane antigen, Epstein-Barr virus; D014763:Viral Matrix Proteins; C432165:pyrazolanthrone; D048031:JNK Mitogen-Activated Protein Kinases; D048055:Mitogen-Activated Protein Kinase 8