The human herpes virus 8-encoded viral FLICE-inhibitory protein induces cellular transformation via NF-kappaB activation.
Infection with human herpes virus 8 (HHV8) has been associated with Kaposi's sarcoma, primary effusion lymphoma, and multicentric Castleman's disease. HHV8 encodes for a viral FLICE-inhibitory protein (vFLIP), designated K13, which resembles the prodomain of caspase-8 in structure and has been shown to protect cells against death receptor-induced apoptosis in vitro and in vivo. In this report, we present evidence that HHV8 vFLIP also possesses the unique ability of transforming Rat-1 and Balb/3T3 fibroblast cells, which is not shared by other vFLIPs. Rat-1 cells expressing HHV8 vFLIP form colonies in soft agar and form tumors in nude mice. The transforming ability of HHV8 vFLIP is associated with the activation of the NF-kappaB pathway and is blocked by molecular and chemical inhibitors of this pathway. Our results suggest that vFLIP K13 has activity beyond its role as an inhibitor of death receptor signaling and may play a causative role in the pathogenesis of HHV8-associated malignancies. Furthermore, inhibitors of the NF-kappaB pathway may have a role in the treatment of malignancies linked to HHV8 infection.
Sun
Qinmiao
Q
Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, Texas 75390-8593, USA.
Zachariah
Sunny
S
Chaudhary
Preet M
PM
D000256:Adenoviridae / Q000235:genetics; D000362:Agar / Q000494:pharmacology; D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis; D015139:Blotting, Southern; D015153:Blotting, Western; D053181:Caspase 8; D020169:Caspases / Q000378:metabolism*; D016923:Cell Death; D002455:Cell Division; D002460:Cell Line; D002471:Cell Transformation, Neoplastic; D005822:Genetic Vectors; D019288:Herpesvirus 8, Human / Q000378:metabolism*; D006801:Humans; D008156:Luciferases / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008858:Microscopy, Phase-Contrast; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000378:metabolism*; D051381:Rats; D012190:Retroviridae / Q000235:genetics; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction; D013997:Time Factors; D014764:Viral Proteins / Q000235:genetics* / Q000494:pharmacology*
D016328:NF-kappa B; D014764:Viral Proteins; C481275:viral FLIP protein, Human herpesvirus 8; D000362:Agar; D008156:Luciferases; C505530:CASP8 protein, human; C505526:Casp8 protein, mouse; C505528:Casp8 protein, rat; D053181:Caspase 8; D020169:Caspases