G-protein-coupled Receptor of Kaposi's Sarcoma-Associated Herpesvirus Is a Viral Oncogene and Angiogenesis Activator

Nature. 1998 Jan 1;391(6662):86-9. doi: 10.1038/34193.

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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • 3T3 Cells
  • Animals
  • Calcium-Calmodulin-Dependent Protein Kinases / metabolism
  • Cell Transformation, Neoplastic
  • Culture Media, Conditioned
  • Endothelial Growth Factors / metabolism
  • Female
  • GTP-Binding Proteins / metabolism
  • JNK Mitogen-Activated Protein Kinases
  • Lymphokines / metabolism
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Mitogen-Activated Protein Kinase 1 / metabolism
  • Mitogen-Activated Protein Kinases*
  • Neoplasm Transplantation
  • Neovascularization, Pathologic / virology*
  • Oncogenes*
  • Receptors, Chemokine / genetics
  • Receptors, Chemokine / physiology*
  • Sarcoma, Kaposi / pathology
  • Sarcoma, Kaposi / virology*
  • Signal Transduction
  • Transfection
  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factors
  • Viral Proteins / genetics
  • Viral Proteins / physiology*
  • p38 Mitogen-Activated Protein Kinases

Substances

  • Culture Media, Conditioned
  • Endothelial Growth Factors
  • Lymphokines
  • ORF74 protein, Human herpesvirus 8
  • Receptors, Chemokine
  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factors
  • Viral Proteins
  • Calcium-Calmodulin-Dependent Protein Kinases
  • JNK Mitogen-Activated Protein Kinases
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinases
  • p38 Mitogen-Activated Protein Kinases
  • GTP-Binding Proteins