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 1 alpha

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 disc losing transforming mechanisms, and they may also afford the possibility of investigating the relationship between transforming pathways and angiogene sis. In this regard, we have recently observed that a constitutively active G protein-coupled receptor (GPCR) encoded by the Kaposi's sarcoma-associat ed herpes virus (KSHV)/human herpes virus 8 is oncogenic and stimulates ang iogenesis by increasing the secretion of vascular endothelial growth factor (VEGF), which is a key angiogenic stimulator and a critical mitogen for th e development of Kaposi's sarcoma. Here we show that the KSHV GPCR enhances the expression of VEGF by stimulating the activity of the transcription fa ctor hypoxia-inducible factor (HIF)-1 alpha, which activates transcription from a hypoxia response element within the 5'-flanking region of the VEGF p romoter. Stimulation of HIF-1 alpha by the KSHV GPCR involves the phosphory lation of its regulatory/inhibitory domain by the p38 and mitogen-activated protein kinase (MAPK) signaling pathways, thereby enhancing its transcript ional activity, Moreover, specific inhibitors of the p38 (SKF86002) and MAP K (PD98059) pathways are able to inhibit the activation of the transactivat ing activity of HIF-1 alpha induced by the KSHV GPCR, as well as the VEGF e xpression and secretion in cells overexpressing this receptor. These findin gs suggest that the KSHV GPCR oncogene subverts convergent physiological pa thways leading to angiogenesis and provide the first insight into a mechani sm whereby growth factors and oncogenes acting upstream from MAPK, as well as inflammatory cytokines and cellular stresses that activate p38, can inte ract with the hypoxia-dependent machinery of angiogenesis, These results ma y also help to identify novel targets for the development of antiangiogenic therapies aimed at the treatment of Kaposi's sarcoma and other neoplastic diseases.