Human cytomegalovirus-encoded chemokine receptor US28 promotes tumorigenesis.
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 protein-uncoupled 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 and/or promote HCMV-associated tumor progression.
Maussang
David
D
Leiden/Amsterdam Center for Drug Research, Division of Medicinal Chemistry, Faculty of Sciences, Vrije Universiteit, De Boelelaan 1083, 1081 HV, Amsterdam, The Netherlands.
Verzijl
Dennis
D
van Walsum
Marijke
M
Leurs
Rob
R
Holl
Jens
J
Pleskoff
Olivier
O
Michel
Detlef
D
van Dongen
Guus A M S
GA
Smit
Martine J
MJ
D000818:Animals; D019556:COS Cells; D002453:Cell Cycle; D002471:Cell Transformation, Neoplastic; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D003587:Cytomegalovirus; D005260:Female; D015870:Gene Expression; D020962:Heterotrimeric GTP-Binding Proteins / Q000378:metabolism; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D041681:NIH 3T3 Cells; D009369:Neoplasms / Q000098:blood supply / Q000378:metabolism* / Q000473:pathology*; D009389:Neovascularization, Pathologic; D010641:Phenotype; D010940:Plant Proteins; D011401:Promoter Regions, Genetic / Q000235:genetics; D019707:Receptors, Chemokine / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism; D014764:Viral Proteins / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D010940:Plant Proteins; D019707:Receptors, Chemokine; C411191:US28 receptor, Cytomegalovirus; D042461:Vascular Endothelial Growth Factor A; D014764:Viral Proteins; C101691:MMK4 protein, Medicago sativa; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D020962:Heterotrimeric GTP-Binding Proteins