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

Publication: Research - peer-reviewJournal article – Annual report year: 2010

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Cell transformation mediated by the Epstein-Barr virus G protein-coupled receptor BILF1 is dependent on constitutive signaling. / Lyngaa, Rikke Birgitte; Nørregaard, K.; Kristensen, Martin; Kubale, V.; Rosenkilde, M.M.; Kledal, Thomas N.

In: Oncogene, Vol. 29, No. 31, 2010, p. 4388-4398.

Publication: Research - peer-reviewJournal article – Annual report year: 2010

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Lyngaa, Rikke Birgitte; Nørregaard, K.; Kristensen, Martin; Kubale, V.; Rosenkilde, M.M.; Kledal, Thomas N / Cell transformation mediated by the Epstein-Barr virus G protein-coupled receptor BILF1 is dependent on constitutive signaling.

In: Oncogene, Vol. 29, No. 31, 2010, p. 4388-4398.

Publication: Research - peer-reviewJournal article – Annual report year: 2010

Bibtex

@article{955aac6a2c2c4de48ed5bb8d5e7ce7af,
title = "Cell transformation mediated by the Epstein-Barr virus G protein-coupled receptor BILF1 is dependent on constitutive signaling",
keywords = "G protein-coupled receptor, Epstein-Barr virus, signaling, cell transformation, constitutive activity, VEGF",
publisher = "Nature Publishing Group",
author = "Lyngaa, {Rikke Birgitte} and K. Nørregaard and Martin Kristensen and V. Kubale and M.M. Rosenkilde and Kledal, {Thomas N}",
year = "2010",
doi = "10.1038/onc.2010.173",
volume = "29",
number = "31",
pages = "4388--4398",
journal = "Oncogene",
issn = "0950-9232",

}

RIS

TY - JOUR

T1 - Cell transformation mediated by the Epstein-Barr virus G protein-coupled receptor BILF1 is dependent on constitutive signaling

A1 - Lyngaa,Rikke Birgitte

A1 - Nørregaard,K.

A1 - Kristensen,Martin

A1 - Kubale,V.

A1 - Rosenkilde,M.M.

A1 - Kledal,Thomas N

AU - Lyngaa,Rikke Birgitte

AU - Nørregaard,K.

AU - Kristensen,Martin

AU - Kubale,V.

AU - Rosenkilde,M.M.

AU - Kledal,Thomas N

PB - Nature Publishing Group

PY - 2010

Y1 - 2010

N2 - Epstein-Barr virus (EBV) open reading frame BILF1 encodes a seven trans-membrane (TM) G protein-coupled receptor that signals with high constitutive activity through G alpha(i) (Beisser et al., 2005; 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. Oncogene (2010) 29, 4388-4398; doi: 10.1038/onc.2010.173; published online 14 June 2010

AB - Epstein-Barr virus (EBV) open reading frame BILF1 encodes a seven trans-membrane (TM) G protein-coupled receptor that signals with high constitutive activity through G alpha(i) (Beisser et al., 2005; 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. Oncogene (2010) 29, 4388-4398; doi: 10.1038/onc.2010.173; published online 14 June 2010

KW - G protein-coupled receptor

KW - Epstein-Barr virus

KW - signaling

KW - cell transformation

KW - constitutive activity

KW - VEGF

U2 - 10.1038/onc.2010.173

DO - 10.1038/onc.2010.173

JO - Oncogene

JF - Oncogene

SN - 0950-9232

IS - 31

VL - 29

SP - 4388

EP - 4398

ER -