EPSTEIN-BARR-VIRUS LATENT MEMBRANE PROTEIN-1 TRIGGERS AP-1 ACTIVITY VIA THE C-JUN N-TERMINAL KINASE CASCADE

The Epstein-Barr virus latent membrane protein-1 (LMP-1) is an integra l membrane protein which transforms fibroblasts and is essential for E BV-mediated B-cell immortalization, LMP-1 has been shown to trigger ce llular NF-kappa B activity which, however, cannot fully explain the on cogenic potential of LMP-1. Here we show that LMP-1 induces the activi ty of the AP-1 transcription factor, a dimer of Jun/Jun or Jun/Fos pro teins, LMP-1 effects on AP-1 are mediated through activation of the c- Jun N-terminal kinase (JNK) cascade, but not the extracellular signal- regulated kinase (Erk) pathway, Consequently, LMP-1 triggers the activ ity of the c-Jun N-terminal transactivation domain which is known to b e activated upon JNK-mediated phosphorylation, Deletion analysis indic ates that the 55 C-terminal amino acids of the LMP-1 molecule, but not its TRAF interaction domain, are essential for AP-1 activation, JNK-m ediated transcriptional activation of AP-1 is the direct output of LMP -1-triggered signaling, as shown by an inducible LMP-1 mutant, Using a tetracycline-regulated LMP-1 allele, we demonstrate that JNK is also an effector of non-cytotoxic LMP-1 signaling in B cells, the physiolog ical target cells of EBV, In summary, our data reveal a novel effector of LMP-1, the SEK/JNK/c-Jun/AP-1 pathway, which contributes to our un derstanding of the immortalizing and transforming potential of LMP-1.