G-protein-coupled receptor of Kaposi's sarcoma-associated herpesvirus is a viral oncogene and angiogenesis activator

Abstract

The Kaposi's sarcoma-associated herpesvirus (KSHV/HHV8) is a gamma-2 herpesvirus that is implicated in the pathogenesis of Kaposi's sarcoma and of primary effusion B-cell lymphomas (PELs). KSHV infects malignant and progenitor cells of Kaposi's sarcoma and PEL, it encodes putative oncogenes and genes that may cause Kaposi's sarcoma pathogenesis by stimulating angiogenesis. The G-protein-coupled receptor encoded by an open reading frame (ORF 74) of KSHV is expressed in Kaposi's sarcoma lesions and in PEL and stimulates signalling pathways linked to cell proliferation in a constitutive (agonist-independent) way. Here we show that signalling by this KSHV G-protein-coupled receptor leads to cell transformation and tumorigenicity, and induces a switch to an angiogenic phenotype mediated by vascular endothelial growth factor, an angiogenesis and Kaposi's-spindle-cell growth factor. We find that this receptor can activate two protein kinases, JNK/SAPK and p38MAPK, by triggering signalling cascades like those induced by inflammatory cytokines that are angiogenesis activators and mitogens for Kaposi's sarcoma cells and B cells. We conclude that the KSHV G-protein-coupled receptor is a viral oncogene that can exploit cell signalling pathways to induce transformation and angiogenesis in KSHV-mediated oncogenesis.

The role of Kaposi's sarcoma-associated herpesvirus/human herpesvirus-8 regulator of transcription activation (RTA) in control of gene expression

“…These proinflammatory mediators have been suggested to play a key role in the autocrine and paracrine maintenance of KS tumor. Several of these gene products have also been demonstrated to induce neoangiogenesis Arvanitakis et al, 1997;Boshoff et al, 1997;Bais et al, 1998). Thus, the control of latent to lytic replication in HHV-8-infected cells, and the expression of lytic gene products could play a key role in KS disease pathogenesis.…”

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

“…For example, it appears to couple to Gq in Cos-1 and HEK 293T cells, and activates the stress-activated kinases JNK and p38 in the later (Arvanitakis et al, 1997;Bais et al, 1998;Burger et al, 1999). In endothelial cells, vGPCR clearly signals via Gi and leads to increased cell survival (Couty et al, 2001;Montaner et al, 2001).…”

“…It is known that KSHV vGPCR activates ERK-1/2 in COS-7, but not in HEK 293 cells (Bais et al, 1998;Sodhi et al, 2000), and we have recently shown constitutive activation of ERK-1/2 and p38 by vGPCR in PEL cells (Cannon et al, 2003). To determine which vGPCR downstream events required ERK-1/2 activation, BC3.14 cells were transfected with the indicated reporter constructs in Figure 3 and subjected to 50 mm PD98059, a specific inhibitor of ERK-1/2.…”

Pathogenetic Influences of Human Herpesvirus 8 (HHV-8) in Prostate Cancer Progression

“…In regard to this work, it is important to note that an association between HHV-8 and prostate cancer has not been established. The viral G protein-couple receptor (vGPCR) is a lytic protein that promotes cellular proliferation by simultaneously activating several signal transduction pathways, including MAPK, AKT and the transcription factor NF-κB (116)(117)(118). A second lytic protein, viral IL-6 (vIL-6) is a structural and functional homolog to cellular IL-6 (119) and through activation of the STAT3 pathway also contributes to cellular growth (120,121).…”