title: Epstein-Barr virus-encoded LMP1 promotes cisplatin-induced caspase activation through JNK and NF-kappaB signaling pathways.
abstract: Our previous studies have shown that Epstein-Barr virus (EBV)-encoded latent membrane protein 1 (LMP1) potentiates chemotherapeutic agent-induced apoptosis in human cell lines of epithelial origin: cervical carcinoma-derived HeLa cells and nasopharyngeal carcinoma-derived TW03 cells. LMP1 acted upstream of caspase-dependent mitochondrial perturbation, and the effect was mapped to the C-terminal signaling domain of LMP1, designated CTAR2. CTAR2 is known to engage the c-Jun N-terminal kinase (JNK) and NF-kappaB pathways, and we show here that SP600125, a selective JNK inhibitor, suppresses LMP1 potentiation of cisplatin-induced mitochondrial damage and caspase activation in HeLa cells. Moreover, the potentiation of cisplatin-triggered caspase activation was blocked by Bay11-7082, a potent inhibitor of NF-kappaB. Similar results were obtained when a dominant negative form of IkappaB, a specific repressor of NF-kappaB, was co-expressed with LMP1. The current data support the notion that LMP1 modifies stress-induced apoptosis in epithelial cells through molecular interactions downstream of its C-terminal signaling domain.
authors.affiliation: Department of Microbiology, Tumor and Cell Biology, Box 280, Karolinska Institutet, 171 77 Stockholm, Sweden.
authors.forename: Xiangning
authors.initials: X
authors.lastname: Zhang
authors.forename: Duangmanee
authors.initials: D
authors.lastname: Sanmun
authors.forename: LiFu
authors.initials: L
authors.lastname: Hu
authors.forename: Bengt
authors.initials: B
authors.lastname: Fadeel
authors.forename: Ingemar
authors.initials: I
authors.lastname: Ernberg
mesh_terms: D020169:Caspases / Q000187:drug effects* / Q000378:metabolism*; D002945:Cisplatin / Q000008:administration & dosage*; D004789:Enzyme Activation / Q000187:drug effects; D006367:HeLa Cells; D006801:Humans; D048670:MAP Kinase Kinase 4 / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D014763:Viral Matrix Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: C037662:EBV-associated membrane antigen, Epstein-Barr virus; D016328:NF-kappa B; D014763:Viral Matrix Proteins; D048670:MAP Kinase Kinase 4; D020169:Caspases; D002945:Cisplatin