NEGATIVE REGULATION OF HYPOXIA-INDUCIBLE GENES BY THE VON-HIPPEL-LINDAU PROTEIN

Inactivation of the von Hippel-Lindau protein (pVHL) has been implicat ed in the pathogenesis of renal carcinomas and central nervous system hemangioblastomas. These are highly vascular tumors which overproduce angiogenic peptides such as vascular endothelial growth factor/vascula r permeability factor (VEGF/VPF), Renal carcinoma cells lacking wild-t ype pVHL were found to produce mRNAs encoding VEGF/VPF, the glucose tr ansporter GLUT1, and the platelet-derived growth factor B chain under both normoxic and hypoxic conditions, Reintroduction of wild-type, but not mutant, pVHL into these cells specifically inhibited the producti on of these mRNAs under normoxic conditions, thus restoring their prev iously described hypoxia-inducible profile, Thus, pVHL appears to play a critical role in the transduction of signals generated by changes i n ambient oxygen tension.