REGULATION OF HYPOXIA-INDUCIBLE FACTOR 1-ALPHA IS MEDIATED BY AN O-2-DEPENDENT DEGRADATION DOMAIN VIA THE UBIQUITIN-PROTEASOME PATHWAY

Hypoxia induces a group of physiologically important genes such as ery thropoietin and vascular endothelial growth factor, These genes are tr anscriptionally upregulated by hypoxia-inducible factor 1 (HIF-1), a g lobal regulator that belongs to the basic helix-loop-helix PAS family. Although HIF-1 is a heterodimer composed of alpha and beta subunits, its activity is primarily determined by hypoxia-induced stabilization of HIF-1 alpha, which is otherwise rapidly degraded in oxygenated cell s. We report the identification of an oxygen-dependent degradation (OD D) domain within HIF-1 alpha that controls its degradation by the ubiq uitin-proteasome pathway. The ODD domain consists of approximate to 20 0 amino acid residues, located in the central region of HIF-1 alpha. B ecause portions of the domain independently confer degradation of HIF- 1 alpha, deletion of this entire region is required to give rise to a stable HIF-1 alpha, capable of heterodimerization, DNA-binding, and tr ansactivation in the absence of hypoxic signaling. Conversely, the ODD domain alone confers oxygen-dependent instability when fused to a sta ble protein, Gal4. Hence, the ODD domain plays a pivotal role for regu lating HIF-1 activity and thereby may provide a means of controlling g ene expression by changes in oxygen tension.