HYPOXIA-INDUCIBLE PROTEIN BINDING TO VASCULAR ENDOTHELIAL GROWTH-FACTOR MESSENGER-RNA AND ITS MODULATION BY THE VON-HIPPEL-LINDAU PROTEIN

Hypoxia induces an increase in the stability of the mRNA encoding vasc ular endothelial growth factor (VEGF). We have previously demonstrated that a 500-base region of the 3'-untranslated region of VEGF mRNA tha t is critical for stabilization of VEGF mRNA in an in vitro degradatio n assay forms a RNA-protein complex in a hypoxia-inducible fashion. We report here the identification of three adenylate-uridylate-rich RNA elements within this region that form an identical or closely related hypoxia-inducible RNA-protein complex. This complex is constitutively elevated in a tumor cell line lacking the wild type von Hippel-Lindau tumor suppressor gene and in which VEGF mRNA is constitutively stabili zed, Furthermore, the glucose transporter-1 mRNA, which is also stabil ized by hypoxia, forms a hypoxia-inducible RNA-protein complex with si milar sequence and protein binding characteristics to that described f or VEGF mRNA. Finally, RNA affinity purification and UV cross linking were used to identify three proteins of 32, 28, and 17 kDa that are de rived from this hypoxia-inducible RNA-protein complex.