Human cytomegalovirus-encoded chemokine receptor US28 promotes tumorigenesis

Abstract

Human cytomegalovirus (HCMV) is a widely spread herpesvirus, suggested to play a role in tumor progression. US28, a chemokine receptor encoded by HCMV, binds a broad spectrum of chemokines and constitutively activates various pathways linked to proliferation. Our studies reveal that expression of US28 induces a proangiogenic and transformed phenotype by up-regulating the expression of vascular endothelial growth factor and enhancing cell growth and cell cycle progression. US28-expressing cells promote tumorigenesis when injected into nude mice. The G proteinuncoupled constitutively inactive mutant of US28, induces delayed and attenuated tumor formation, indicating the importance of constitutive receptor activity in the early onset of tumor development. Importantly, also in glioblastoma cells infected with the newly isolated clinical HCMV strain Titan, US28 was shown to be involved in the HCMV-induced angiogenic phenotype. Hence, the constitutively activated chemokine receptor US28 might act as a viral oncogene and enhance and͞or promote HCMV-associated tumor progression.cancer ͉ G protein-coupled receptor ͉ VEGF ͉ viral infection ͉ drug target

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

“…In contrast, control cells and cells expressing the 'EAT' receptor exhibited a slowly decreasing cell number after day 5. Previously, both US28 and ORF74 have been shown to induce VEGF expression (Sodhi et al, 2000;Maussang et al, 2006). To investigate the effect of receptor expression on VEGF secretion, conditioned media from NIH3T3 pool clones were assayed at indicated days over a 21-day period.…”

“…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).…”

“…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;.…”

“…In ORF74, the 'DRY' motif sequence is 'VRY' (Val-ArgTyr) and in BILF1 the sequence is 'EKT' (Glu-LysThr) (Paulsen et al, 2005). Alternative 'DRY' sequences have previously been shown to be associated with constitutive activity Maussang et al, 2006). It is noteworthy that replacing the 'DRY' sequence in the human CXC chemokine receptor CXCR2 with the 'VRY' sequence from ORF74 resulted in a constitutively active receptor, capable of mediating cell transformation (Burger et al, 1999).…”

The role of CMV in glioblastoma and implications for immunotherapeutic strategies

“…During CMV infection, US28 has constitutive activity resulting in G-protein dependent signaling. Overexpression of US28 in glioma cells promoted secretion of vascular endothelial growth factor (VEGF) 30 , activated signal transducer and activator of transcription (STAT)3, and resulted in increased GBM cell invasiveness. 31 US28 expression also accelerates glioma growth.…”