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 transcription factors that regulate several cellular responses to oxygen tension. Hypoxia inducible factor-1 (HIF-1) is a heterodimeric protein activated by hypoxia. Levels of HIF-1 are regulated by removal of the HIF-1alpha subunit through ubiquination and proteasomal destruction under normoxic conditions. Hypoxia inhibits the ubiquination of HIF-1alpha, preventing its destruction and allowing it to bind to hypoxia-responsive elements in gene promoter, enhancer, and intronic sequences. HIF-1 induces the expression of the hypoxia responsive genes vascular endothelial growth factor and erythropoietin. Its dysregulation has been implicated in von Hippel-Lindau disease. Nuclear factor kappaB (NFkappaB) is a family of pleotropic, dimeric transcription factors, and has a complex pattern of regulation. Under normoxic conditions, NFkappaB is bound to one of several inhibitory proteins (e.g., IkappaB) that prevent its nuclear translocation. Hyperoxia or elevations of ROS cause the ubiquination and destruction of the inhibitory proteins, freeing NFkappaB and allowing it to bind to target gene promoters. Hyperoxia in cell and animal models and acute lung injury in humans induce the expression of multiple proinflammatory cytokines through NFkappaB-dependent mechanisms. Although HIF-1 and NFkappaB respond to changes in pO(2), the precise nature of the oxygen sensing and transduction pathways is unclear in both cases. Both heme-protein and redox-sensitive mechanisms have been proposed. Improved understanding of oxygen-sensitive gene regulation may suggest targeted therapies for human disease.