Elucidation of the c-Jun N-terminal kinase pathway mediated by Estein-Barr virus-encoded latent membrane protein 1.
Epstein-Barr virus (EBV) is associated with several human diseases including infectious mononucleosis and nasopharyngeal carcinoma. EBV-encoded latent membrane protein 1 (LMP1) is oncogenic and indispensable for cellular transformation caused by EBV. Expression of LMP1 in host cells constitutively activates both the c-Jun N-terminal kinase (JNK) and NF-kappaB pathways, which contributes to the oncogenic effect of LMP1. However, the underlying signaling mechanisms are not very well understood. Based mainly on overexpression studies with various dominant-negative constructs, LMP1 was generally thought to functionally mimic members of the tumor necrosis factor (TNF) receptor superfamily in signaling. In contrast to the prevailing paradigm, using embryonic fibroblasts from different knockout mice and the small interfering RNA technique, we find that the LMP1-mediated JNK pathway is distinct from those mediated by either TNF-alpha or interleukin-1. Moreover, we have further elucidated the LMP1-mediated JNK pathway by demonstrating that LMP1 selectively utilizes TNF receptor-associated factor 6, TAK1/TAB1, and c-Jun N-terminal kinase kinases 1 and 2 to activate JNK.
Wan
Jun
J
Department of Biochemistry, Hong Kong University of Science and Technology, Hong Kong, People's Republic of China.
Sun
Luguo
L
Mendoza
Jennifer Woo
JW
Chui
Yiu Loon
YL
Huang
Dolly P
DP
Chen
Zhijian J
ZJ
Suzuki
Nobutaka
N
Suzuki
Shinobu
S
Yeh
Wen-Chen
WC
Akira
Shizuo
S
Matsumoto
Kunihiro
K
Liu
Zheng-Gang
ZG
Wu
Zhenguo
Z
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins / Q000378:metabolism; D004854:Herpesvirus 4, Human / Q000378:metabolism*; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D048688:MAP Kinase Kinase 7; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D017433:Protein Structure, Secondary; D011506:Proteins / Q000378:metabolism; D048029:TNF Receptor-Associated Factor 6; D014763:Viral Matrix Proteins / Q000378:metabolism*; D000099151:MAP Kinase Kinase Kinase 7
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D048031:JNK Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D048688:MAP Kinase Kinase 7; D020930:MAP Kinase Kinase Kinases; D020929:Mitogen-Activated Protein Kinase Kinases; D020928:Mitogen-Activated Protein Kinases; D011506:Proteins; D048029:TNF Receptor-Associated Factor 6; D014763:Viral Matrix Proteins; D000099151:MAP Kinase Kinase Kinase 7; C037662:EBV-associated membrane antigen, Epstein-Barr virus; C410585:TAB2 protein, human; C482559:MAP2K4 protein, human; C482569:MAP2K7 protein, human