Oxygen regulation of gene expression: A study in opposites

Oxygen is crucial to aerobic metabolism, but excesses of oxygen or reactive oxygen species (ROS) can injure cells. This minireview addresses two trans cription factors that regulate several cellular responses to oxygen tension . Hypoxia inducible factor-1 (HIF-1) is a heterodimeric protein activated b y hypoxia, Levels of HIF-1 are regulated by removal of the HIF-1 alpha subu nit through ubiquination and proteasomal destruction under normoxic conditi ons. Hypoxia inhibits the ubiquination of HIF-1 alpha, preventing its destr uction and allowing it to bind to hypoxia-responsive elements in gene promo ter, enhancer, and intronic sequences. HIF-1 induces the expression of the hypoxia responsive genes vascular endothelial growth factor and erythropoie tin. Its dysregulation has been implicated in von Hippel-Lindau disease. Nu clear factor kappa B (NF kappa B) is a family of pleotropic, dimeric transc ription factors, and has a complex pattern of regulation. Under normoxic co nditions, NF kappa B is bound to one of several inhibitory proteins (e.g., I kappa B) that prevent its nuclear translocation. Hyperoxia or elevations of ROS cause the ubiquination and destruction of the inhibitory proteins, f reeing NF kappa B and allowing it to bind to target gene promoters. Hyperox ia in cell and animal models and acute lung injury in humans induce the exp ression of multiple proinflammatory cytokines through NF kappa B-dependent mechanisms. Although HIF-1 and NF kappa B respond to changes in pO(2), the precise nature of the oxygen sensing and transduction pathways is unclear i n both cases. Both heme-protein and redox-sensitive mechanisms have been pr oposed. Improved understanding of oxygen-sensitive gene regulation may sugg est targeted therapies for human disease. (C) 2000 Academic Press.