Kaposi's sarcoma associated herpesvirus G protein-coupled receptor immortalizes human endothelial cells by activation of the VEGF receptor-2/ KDR.
The G protein-coupled receptor oncogene (vGPCR) of the Kaposi's sarcoma (KS) associated herpesvirus (KSHV), an oncovirus implicated in angioproliferative neoplasms, induces angiogenesis by VEGF secretion. Accordingly, we found that expression of vGPCR in human umbilical vein endothelial cells (HUVEC) leads to immortalization with constitutive VEGF receptor-2/ KDR expression and activation. vGPCR immortalization was associated with anti-senescence mediated by alternative lengthening of telomeres and an anti-apoptotic response mediated by vGPCR constitutive signaling and KDR autocrine signaling leading to activation of the PI3K/AKT pathway. In the presence of the KS growth factor VEGF, this mechanism can sustain suppression of signaling by the immortalizing gene. We conclude that vGPCR can cause an oncogenic immortalizing event and recapitulate aspects of the KS angiogenic phenotype in human endothelial cells, pointing to this gene as a pathogenic determinant of KSHV.
Bais
Carlos
C
Laboratory of Viral Oncogenesis, Department of Medicine, Weill Medical College of Cornell University, 1300 York Avenue, New York, NY 10021, USA.
Van Geelen
Albert
A
Eroles
Pilar
P
Mutlu
Agata
A
Chiozzini
Chiara
C
Dias
Sergio
S
Silverstein
Roy L
RL
Rafii
Shahin
S
Mesri
Enrique A
EA
D017209:Apoptosis; D002471:Cell Transformation, Neoplastic; D002478:Cells, Cultured; D016228:Endothelial Growth Factors / Q000378:metabolism; D004730:Endothelium, Vascular / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D019288:Herpesvirus 8, Human / Q000472:pathogenicity; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D008222:Lymphokines / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D019707:Receptors, Chemokine / Q000502:physiology*; D012190:Retroviridae / Q000235:genetics; D012514:Sarcoma, Kaposi / Q000378:metabolism / Q000473:pathology / Q000821:virology; D015398:Signal Transduction; D019098:Telomerase / Q000378:metabolism; D016615:Telomere / Q000378:metabolism; D014471:Umbilical Veins; D042461:Vascular Endothelial Growth Factor A; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism*; D042442:Vascular Endothelial Growth Factors; D014764:Viral Proteins / Q000502:physiology*
D016228:Endothelial Growth Factors; D036341:Intercellular Signaling Peptides and Proteins; D008222:Lymphokines; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D019707:Receptors, Chemokine; D019098:Telomerase; D042461:Vascular Endothelial Growth Factor A; D040301:Vascular Endothelial Growth Factor Receptor-2; D042442:Vascular Endothelial Growth Factors; D014764:Viral Proteins; C115448:G protein-coupled receptor, Human herpesvirus 8; C494918:AKT1 protein, human