THESIS
2004
xvi, 128 leaves : ill. (some col.) ; 30 cm
Abstract
Epstein-Barr virus (EBV) is associated with several human diseases including infectious mononucleosis, nasopharyngeal carcinoma and Hodgkin's disease. 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 JNK and NF-κB pathways, which contributes to the oncogenic effect of LMP1. However, the underlying signaling mechanisms are not very well understood. Based mainly on over-expression studies with various "dominant-negative" constructs, LMP1 was generally thought to functionally mimic members of the tumor necrosis factor (TNF) receptor superfamily in cellular signaling. In contrast to the prevailing paradigm, using embryonic fibroblasts from different knocko...[
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Epstein-Barr virus (EBV) is associated with several human diseases including infectious mononucleosis, nasopharyngeal carcinoma and Hodgkin's disease. 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 JNK and NF-κB pathways, which contributes to the oncogenic effect of LMP1. However, the underlying signaling mechanisms are not very well understood. Based mainly on over-expression studies with various "dominant-negative" constructs, LMP1 was generally thought to functionally mimic members of the tumor necrosis factor (TNF) receptor superfamily in cellular signaling. In contrast to the prevailing paradigm, using embryonic fibroblasts from different knockout mice and the siRNA technique, we find that the LMP1-mediated JNK pathway is distinct from those mediated by either TNFα or interleukin-1. By yeast-two-hybrid screening, we also found an adaptor protein that can bind to LMP1 directly. Moreover, we have further elucidated the LMP1-mediated JNK pathway by demonstrating that LMP1 selectively utilizes BS69, TRAF6, TAK1/TAB1, and JNKK1/2 to activate JNK.
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