Identification and clinical application of a novel regulatory proteins under hypoxic stress

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Hypoxia-inducible factor (HIF)-1α is a transcription factor that controls expression of genes responsive to low oxygen tension, including vascular endothelial growth factor, erythropoien, and glycolytic enzymes. The activation of HIF-1a is regulated by binding to the transcriptional co-activator cAMP response element-binding protein-binding protein (CBP)/p300. Using the yeast two-hybrid screening system, we found that the inhibitory domain of HIF-1α strongly interacted with the C-terminal domain of histone deacetylase (HDAC)7. The o-nitrophenyl β-D-galactopyranoside assay revealed that regions containing amino acids 735-785 of HIF-1α and amino acids 669-952 of HDAC7 were minimum contact sites of the interaction. The binding of HDAC7 with HIF-1α was reproduced in HEK293 cells grown under normoxic and hypoxic condition (2%, O2). HDAC7 bound solely to HIF-1α among other HIF-α family members, including HIF-2α and HIF-3α, whereas HIF-1α only interacted with HDAC7 in the class HDAC family. Although HDAC7 was localized dominantly in the cytoplasm at normal oxygen concentrations, In the nucleus, HDAC7 increased transcriptional activity of HIF-1α through the formation of a complex with HIF-1α, HDAC7 and p300. Token together, these results indicated that HDAC7 is a novel transcriptional activator of HIF-1α. Currently we found that disscociation of HDAC7 from HDAC7/HIF-1α complex and the export of HDAC7 to the cytoplasm regulated HIF-1α degradation upon the transition from hypoxic oxygen condition to normal oxygen condition (re-oxygenation).