The Kaposi's sarcoma-associated herpes virus G protein-coupled receptor up-regulates vascular endothelial growth factor expression and secretion through mitogen-activated protein kinase and p38 pathways acting on hypoxia-inducible factor 1α

Akrit Sodhi, S. Montaner, V. Patel, M. Zohar, C. Bais, E. A. Mesri, J. S. Gutkind

Research output: Contribution to journalArticle

Abstract

The elucidation of the molecular mechanisms governing the transition from a nonangiogenic to an angiogenic phenotype is central for understanding and controlling malignancies. Viral oncogenes represent powerful tools for disclosing transforming mechanisms, and they may also afford the possibility of investigating the relationship between transforming pathways and angiogenesis. In this regard, we have recently observed that a constitutively active G protein-coupled receptor (GPCR) encoded by the Kaposi's sarcoma-associated herpes virus (KSHV)/human herpes virus 8 is oncogenic and stimulates angiogenesis by increasing the secretion of vascular endothelial growth factor (VEGF), which is a key angiogenic stimulator and a critical mitogen for the development of Kaposi's sarcoma. Here we show that the KSHV GPCR enhances the expression of VEGF by stimulating the activity of the transcription factor hypoxia-inducible factor (HIF)-1α, which activates transcription from a hypoxia response element within the 5'-flanking region of the VEGF promoter. Stimulation of HIF-1α by the KSHV GPCR involves the phosphorylation of its regulatory/inhibitory domain by the p38 and mitogen-activated protein kinase (MAPK) signaling pathways, thereby enhancing its transcriptional activity. Moreover, specific inhibitors of the p38 (SKF86002) and MAPK (PD98059) pathways are able to inhibit the activation of the transactivating activity of HIF-1α induced by the KSHV GPCR, as well as the VEGF expression and secretion in cells overexpressing this receptor. These findings suggest that the KSHV GPCR oncogene subverts convergent physiological pathways leading to angiogenesis and provide the first insight into a mechanism whereby growth factors and oncogenes acting upstream from MAPK, as well as inflammatory cytokines and cellular stresses that activate p38, can interact with the hypoxia-dependent machinery of angiogenesis. These results may also help to identify novel targets for the development of antiangiogenic therapies aimed at the treatment of Kaposi's sarcoma and other neoplastic diseases.

Original languageEnglish (US)
Pages (from-to)4873-4880
Number of pages8
JournalCancer Research
Volume60
Issue number17
StatePublished - Sep 1 2000
Externally publishedYes

Fingerprint

Hypoxia-Inducible Factor 1
p38 Mitogen-Activated Protein Kinases
Vascular Endothelial Growth Factor A
Kaposi's Sarcoma
Up-Regulation
Oncogenes
Satellite Viruses
5' Flanking Region
Response Elements
G-Protein-Coupled Receptors
Mitogen-Activated Protein Kinases
Mitogens
Intercellular Signaling Peptides and Proteins
Transcription Factors
Phosphorylation
Cytokines
Viruses
Phenotype
Human herpesvirus 8 G protein-coupled receptor
Neoplasms

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

The Kaposi's sarcoma-associated herpes virus G protein-coupled receptor up-regulates vascular endothelial growth factor expression and secretion through mitogen-activated protein kinase and p38 pathways acting on hypoxia-inducible factor 1α. / Sodhi, Akrit; Montaner, S.; Patel, V.; Zohar, M.; Bais, C.; Mesri, E. A.; Gutkind, J. S.

In: Cancer Research, Vol. 60, No. 17, 01.09.2000, p. 4873-4880.

Research output: Contribution to journalArticle

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AU - Bais, C.

AU - Mesri, E. A.

AU - Gutkind, J. S.

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