Activation of Hypoxia-inducible Transcription Factor Depends Primarily upon Redox-sensitive Stabilization of Its α Subunit

摘要: Hypoxia-inducible factor 1 (HIF-1) is a heterodimeric transcription that critical for hypoxic induction of number physiologically important genes. We present evidence regulation HIF-1 activity primarily determined by the stability HIF-1α protein. Both and HIF-1β mRNAs were constitutively expressed in HeLa Hep3B cells with no significant hypoxia. However, protein was barely detectable normoxic cells, even when overexpressed, but highly induced whereas levels remained constant, regardless pO2. Hypoxia-induced binding as well rapidly drastically decreased vivo following an abrupt increase to normal oxygen tension. Moreover, short pre-exposure hydrogen peroxide selectively prevented hypoxia-induced via blocking accumulation protein, treatment cell extracts H2O2 had effect on binding. These observations suggest intact redox-dependent signaling pathway required destablization In extracts, DNA reversibly abolished sulfhydryl oxidation. Furthermore, addition reduced thioredoxin enhanced Consistent these results, overexpression Ref-1 significantly potentiated expression reporter construct containing wild-type site. experiments indicate activation involves stabilization