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)-1alpha, which activates transcription from a
hypoxia response element within the 5'-flanking region of the
VEGF promoter. Stimulation of HIF-1alpha 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-1alpha 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.