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

Bais, Carlos; Santomasso, Bianca; Coso, Omar A.; Arvanitakis, Leandros; Raaka, Elizabeth Geras; Gutkind, J. Silvio; Asch, Adam S.; Cesarman, Ethel; Gershengorn, Marvin C.; Mesri, Enrique A.

doi:10.1038/32472

Cited by 200 publications

(321 citation statements)

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“…BILF1 (from human EBV), rhesus EBV BILF1 (rhBILF1), ORF74 and the empty expression vector (pb) were inserted into NIH3T3 cells by retroviral transduction. ORF74 was included as a positive control because of the previously shown oncogenic potential (Arvanitakis et al, 1997;Bais et al, 1998;Cesarman et al, 2000). All three receptors induced foci formation with a higher frequency as compared with the spontaneous background formation in pb-transduced NIH3T3 cells (Figure 1a).…”

Section: Bilf1 Transforms Cellsmentioning

confidence: 96%

“…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;.…”

mentioning

confidence: 99%

“…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).…”

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confidence: 99%

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

et al. 2010

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Epstein-Barr virus (EBV) open reading frame BILF1encodes a seven trans-membrane (TM) G protein-coupled receptor that signals with high constitutive activity through Ga i Paulsen et al., 2005). In this paper, the transforming potential of BILF1 is investigated in vitro in a foci formation assay using retrovirally transduced NIH3T3 cells, as well as in vivo by using nude mice. BILF1 revealed a substantial transforming potential that was dependent on constitutive signaling, as a signaling-deficient mutant completely lost its ability to transform cells in vitro, and an intermediately active triple-mutated receptor possessed an intermediate transforming potential. Furthermore, BILF1 expression induced vascular endothelial growth factor secretion in a constitutively active manner. In nude mice, BILF1 promoted tumor formation in 90% of cases, ORF74 (from Kaposi's sarcoma-associated herpes virus) in 100% of cases, whereas the signaling-deficient receptor resulted in tumor establishment in 40% of cases. These data suggest that BILF1, when expressed during EBV infection, could indeed be involved in the pathogenesis of EBV-associated diseases and malignancies. Furthermore, the correlation between receptor activity and the ability to mediate cell transformation in vitro and tumor formation in vivo supports the idea that inverse agonists for BILF1 could inhibit cell transformation and be relevant therapeutic candidates.

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Section: Bilf1 Transforms Cellsmentioning

confidence: 96%

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confidence: 99%

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confidence: 99%

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

et al. 2010

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“…These include genes expressed during viral latency (LANA-1, a viral cyclin homolog and vFLIP) that act variously to inhibit apoptosis and prevent cell-cycle arrest by pRB [27][28][29], and additional gene products transcribed during lytic replication corresponding to cellular proteins involved in cell cycle progression, apoptosis, proliferation and immune regulation. These include the K1 protein, a viral BCL-2 homolog, a viral GPCR, a viral homolog of IL-6, viral macrophage inflammatory proteins vMIPs, and several viral interferon regulatory factors [30][31][32][33][34]. Notably, mice transfected with the vGPCR develop vascular tumors resembling KS [35], which suggests a key role for this gene product in KS development.…”

Section: The Role Of Hhv-8mentioning

confidence: 99%

“…Notably, mice transfected with the vGPCR develop vascular tumors resembling KS [35], which suggests a key role for this gene product in KS development. Additionally, cells transfected with the vGPCR or K1 secrete vascular endothelial growth factor (VEGF) [34,38], which is overexpressed in KS lesions [36] and activate the VEGF-R2 [37]. The vGPCR and K1 also activate NFκB, which induces transcription of various angiogenic and proinflammatory mediators including VEGF and MMP-9 [30,32,33,38].…”

Section: The Role Of Hhv-8mentioning

confidence: 99%

AIDS-associated Kaposi's sarcoma: Is there still a role for interferon alfa?

Krown

2007

Cytokine & Growth Factor Reviews

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Interferon alfa (IFNA) was one of the first agents to be used therapeutically in AIDS-associated Kaposi's sarcoma (KS) more than 25 years ago, and induces tumor regression in a subset of patients. Although much has been learned about the clinical role of IFNα in KS treatment, little is currently known about the mechanism(s) by which IFNA causes KS regression. This is despite a growing understanding of both KS pathogenesis and relevant IFNA activities. To a large extent other agents have supplanted IFNA as treatments for KS, but there may still remain a therapeutic role for IFNA, possibly in combination with other agents targeting angiogenesis and/or HHV-8-encoded human gene homologs that encode proteins involved in cell cycle regulation and signaling. KeywordsInterferon; Kaposi's sarcoma In 1995, when I was honored as a recipient of the ISICR Milstein Award, the AIDS epidemic had recently begun its 15 th year and the human immunodeficiency virus (HIV-1) had been isolated some 12 years previously [1]. However, the virus associated with Kaposi's sarcoma (KS), the most common AIDS-associated malignancy, had been described less than a year earlier [2], its significance was still in some question and its role in KS development had not been characterized, and the active combination drug regimens with which we now treat HIV infection had not yet become widely available. Recombinant interferon alfa preparations (IFNα2a and IFNα2b), which had received approval from the U.S. Food and Drug Administration (FDA) for treatment of AIDS-associated KS in 1988, were still the only approved drugs for systemic treatment of KS (the chemotherapeutic agent, liposomal doxorubicin, would receive FDA approval later in 1995, as did liposomal daunorubicin in 1996 and paclitaxel in 1997). Now, more than a quarter century after the first published reports describing AIDS and its association with KS [3-6] and our first modestly successful attempts to treat KS with IFNα [7], this agent is used infrequently to treat KS, although it still finds use in HIV-infected individuals co-infected with hepatitis C. In this brief review, I will summarize some of the history of IFNα in the treatment of AIDS-associated KS, concentrating on examples of clinical trials in which I have personally been involved, and consider whether there remains a potentially valuable role for this agent in KS treatment.

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Thrombospondin-1 inhibits Kaposi's sarcoma (KS) cell and HIV-1 Tat-induced angiogenesis and is poorly expressed in KS lesions

et al. 1999

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Kaposi's sarcoma (KS), a neoplasm often associated with iatrogenic and acquired immunosuppression, is characterized by prominent angiogenesis. Angiogenic factors released by both KS and host cells, as well as HHV‐8 and HIV viral products, have been implicated in the pathogenesis of this lesion. Angiogenesis is the result of imbalance among angiogenesis promoters and inhibitors, which disrupts homeostasis. The aim of this study was to investigate the expression and mechanism of KS control of thrombospondin‐1 (TSP), a physiological inhibitor of angiogenesis. Immunohistochemical analysis of four KS lesions showed only spotty reactivity for TSP in the stroma and in less than 10 per cent of lesional blood vessels. In addition, the typical KS spindle cells were not stained. In agreement with these findings, decreased levels of TSP were measured with an ELISA assay in the supernatants of cultured KS cells, compared with endothelial cells. In vitro, TSP inhibited the endothelial cell proliferation and motility induced by KS cell supernatants. TSP also prevented endothelial cell motility induced by Tat, a product of HIV‐1 endowed with angiogenic potential and implicated in the pathogenesis of AIDS‐KS. In vivo, TSP inhibited the angiogenic activity exerted by Tat in the Matrigel sponge model. These results suggest that TSP down‐regulation might be permissive for the development of KS‐associated angiogenesis. Copyright © 1999 John Wiley & Sons, Ltd.

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

Cited by 200 publications

References 1 publication

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

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

AIDS-associated Kaposi's sarcoma: Is there still a role for interferon alfa?

Thrombospondin-1 inhibits Kaposi's sarcoma (KS) cell and HIV-1 Tat-induced angiogenesis and is poorly expressed in KS lesions

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