Activation of NF-κB by the Human Herpesvirus 8 Chemokine Receptor ORF74: Evidence for a Paracrine Model of Kaposi's Sarcoma Pathogenesis

A requirement for NF-κB induction in the production of replication-competent HHV-8 virions

“…Overexpression of the viral G-protein-coupled receptor (vGPCR, ORF 74) has also been shown to induce NF-kB (Montaner et al, 2001;Pati et al, 2001;Schwarz and Murphy, 2001;Chiou et al, 2002;Smit et al, 2002) through the activation of the PI3K/AKT and IKK pathways (Montaner et al, 2001;Pati et al, 2001). vGPCR has been detected in HHV-8-infected PEL cells undergoing lytic replication, consistent with its classification as an early lytic gene product (Sun et al, 1999;Chiou et al, 2002).…”

“…This interaction results in the induction of a survival pathway that effectively inhibits caspase-mediated apoptosis via engagement of the Fas receptor. Overexpression of the early lytic protein vGPCR (Bais et al, 1998;Yang et al, 2000;Guo et al, 2003) has also been shown to induce NF-kB (Montaner et al, 2001;Pati et al, 2001;Schwarz and Murphy, 2001;Chiou et al, 2002;Smit et al, 2002) through the activation of PI3-K/AKT and IKK pathways (Montaner et al, 2001;Pati et al, 2001).…”

Cell transformation mediated by the Epstein–Barr virus G protein-coupled receptor BILF1 is dependent on constitutive signaling

“…US28 signals through Ga q , Ga s and Ga 12/13 , further activating kinases and transcription factors, whereas ORF74 signals through Ga q , Ga s and Ga i , virtually activating the same downstream signal transduction pathways as US28 (Smit et al, 2002;Waldhoer et al, 2002;Streblow et al, 2003;McLean et al, 2004). Furthermore, ORF74 and US28 stimulate the secretion of cytokines and growth factors, including vascular endothelial growth factor (VEGF) (Bais et al, 1998;Sodhi et al, 2000;Pati et al, 2001;Maussang et al, 2006). Most viral 7TM receptors characterized to date are dispensable for viral replication in vitro but are important for viral success in vivo (Davis-Poynter et al, 1997;Vieira et al, 1998;Beisser et al, 1999), presumably because of their function as immune-evasion molecules and/or their involvement in viral dissemination (Bodaghi et al, 1998;.…”

“…Most viral 7TM receptors characterized to date are dispensable for viral replication in vitro but are important for viral success in vivo (Davis-Poynter et al, 1997;Vieira et al, 1998;Beisser et al, 1999), presumably because of their function as immune-evasion molecules and/or their involvement in viral dissemination (Bodaghi et al, 1998;. It has been shown previously that ORF74 from KSHV is a potential oncogene because of its ability to transform cells in vitro (Bais et al, 1998;Pati et al, 2001) and induce Kaposi's sarcoma-like lesions in mice (Yang et al, 2000;Montaner et al, 2003). Interestingly, US28 has also been shown to transform cells in vitro and form tumors in nude mice (Maussang et al, 2006).…”

The KSHV G protein-coupled receptor signals via multiple pathways to induce transcription factor activation in primary effusion lymphoma cells

“…bGAL expression was measured after 48 h using equal amounts of protein extract. A similar control transfection was performed with pRL-TK to ensure that vGPCR has no effect on the herpes simplex virus thymidine kinase-derived promoter used for renilla expression (Montaner et al, 2001;Pati et al, 2001). Given our observation that vGPCR-mediated activation of NFkB is not predominantly Gi-mediated in PEL cells ( Figure 1b, f), we questioned whether PI3K/Akt was involved.…”