Hypoxia-inducible Factor 1α (HIF-1α) Protein Is Rapidly Degraded by the Ubiquitin-Proteasome System under Normoxic Conditions

摘要: The hypoxia-inducible factor 1 transcriptional activator complex (HIF-1) is involved in the activation of erythropoietin and several other hypoxia-responsive genes. HIF-1 composed two protein subunits: HIF-1β/ARNT (aryl hydrocarbon receptor nuclear translocator), which constitutively expressed, HIF-1α, not present normal cells but induced under hypoxic conditions. HIF-1α subunit continuously synthesized degraded normoxic conditions, while it accumulates rapidly following exposure to low oxygen tensions. involvement ubiquitin-proteasome system proteolytic destruction normoxia was studied by use specific inhibitors proteasome system. Lactacystin MG-132 were found protect degradation transferred from hypoxia normoxia. same able induce formation when added cells. Final confirmation regulated obtained ofts20TG R cells, contain a temperature-sensitive mutant E1, ubiquitin-activating enzyme. Exposure ts20 non-permissive temperature rapid progressive accumulation HIF-1. effect on induction binding activity mimicked thiol reducing agentN-(2-mercaptopropionyl)-glycine radical scavenger 2-acetamidoacrylic acid. Furthermore,N-(2-mercaptopropionyl)-glycine gene expression as measured stimulation HIF-1-luciferase vector mRNA Hep 3B These last findings strongly suggest that changes stability subsequent are mediated redox-induced changes.