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 epitheliat origin: cervical carcinoma-derived HeLa cells and nasopharyngeal carcinoina-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-kappa B 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 Bay 11-7082, a potent inhibitor of NF-kappa B Similar results were obtained when a dominant negative form of I kappa B, a specific repressor of NF-kappa B, was co-expressed with LMPI. The current data support the notion that LMPI modifies stress-induced apoptosis in epithelial cells through molecular interactions downstream of its C-terminal signaling domain. (c) 2007 Elsevier Inc. All rights reserved.