VEGF MESSENGER-RNA IS STABILIZED BY RAS AND TYROSINE KINASE ONCOGENES, AS WELL AS BY UV-RADIATION - EVIDENCE FOR DIVERGENT STABILIZATION PATHWAYS

Vascular Endothelial Growth Factor (VEGF) is a pivotal endothelial cel l mitogen that mediates both normal and pathological angiogenesis. Alt hough expressed at very low levels in cells not undergoing vasculariza tion, VEGF mRNA is transiently upregulated and stabilized by a variety of extracellular stimuli, and is persistently upregulated and stabili zed in many human tumor cell lines (White et al., 1995). Here we demon strate that oncogenic activation of tyrosine protein kinases and Ras p roteins induce a 6- to 16-fold increase in the abundance of VEGF mRNA and a 3- to 5-fold increase in the stability of VEGF mRNA, suggesting that persistent activation of signaling pathways induced by these onco proteins accounts for overexpression of VEGF in a significant fraction of human tumors,ln addition to these oncoproteins, ultraviolet (UV) r adiation upregulated and stabilized VEGF mRNA 15- and 5-fold, respecti vely. While the tyrosine kinase inhibitor, genistein, blocked VEGF upr egulation by activated tyrosine protein kinases, and the Ras inhibitor , N-Acetyl-S-trans-farnesyl-L-cysteine (AFC), eliminated VEGF expressi on in cells transformed by v-Ras, neither agent blocked upregulation b y hypoxia or UV radiation. These data argue that multiple divergent pa thways upregulate and stabilize VEGF mRNA.