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Weill Medical College of Cornell University, New York, NY 10021

Address correspondence to Ethel Cesarman, Dept. of Pathology, Weill Medical College of Cornell University, 1300 York Ave., New York, NY 10021. Phone: (212) 746-8838; Fax: (212) 746-4483; email: ecesarm{at}med.cornell.edu

Primary effusion lymphomas (PELs) associated with infection by the Kaposi's sarcoma–associated herpesvirus (KSHV/HHV-8) have constitutive nuclear factor (NF)–B activity that is essential for their survival, but the source of this activity is unknown. We report that viral FADD-like interleukin-1-ß–converting enzyme [FLICE/caspase 8]-inhibitory protein (FLIP) activates NF-B more potently than cellular FLIP in B cells and that it is largely responsible for NF-B activation in latently infected PEL cells. Elimination of vFLIP production in PEL cells by RNA interference results in significantly decreased NF-B activity, down-regulation of essential NF-B–regulated cellular prosurvival factors, induction of apoptosis, and enhanced sensitivity to external apoptotic stimuli. vFLIP is the first virally encoded gene shown to be essential for the survival of naturally infected tumor cells.

Key Words: HHV-8 • NF-kB • Kaposi's sarcoma • AIDS • viral oncogenes

Abbreviations used in this paper: DD, death domain; DED, death effector domain; DISC, death-inducing signaling complex; Doxy, doxycycline; EMSA, electrophoretic mobility shift assay; FA, Fas-associated; FLIP, FADD-like interleukin-1-ß–converting enzyme [FLICE/caspase 8]-inhibitory protein; HTLV-1, human T cell leukemia virus 1; IBL, immunoblastic lymphoma; IKK, IB kinase; KSHV, Kaposi's sarcoma–associated herpesvirus; LANA, latency-associated nuclear antigen; NF, nuclear factor; PARP, poly (ADP-ribose) polymerase; PEL, primary effusion lymphoma; si, small interfering; vCYC, viral cyclin; vGPCR, viral G protein–coupled receptor.

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