Histone deacetylase 7 associates with hypoxia-inducible factor 1alpha and increases transcriptional activity.
Hypoxia-inducible factor (HIF)-1alpha is a transcription factor that controls expression of genes responsive to low oxygen tension, including vascular endothelial growth factor (VEGF), erythropoietin, and glycolytic enzymes. The activity of HIF-1alpha 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-1alpha strongly interacted with the C-terminal domain of histone deacetylase (HDAC) 7. The o-nitrophenyl beta-d-galactopyranoside assay revealed that regions containing amino acids 735-785 of HIF-1alpha and amino acids 669-952 of HDAC7 were minimum contact sites of the interaction. The binding of HDAC7 with HIF-1alpha was reproduced in HEK293 cells grown under normoxic and hypoxic conditions (2% O(2)). HDAC7 bound solely to HIF-1alpha among other HIF-alpha family members, including HIF-2alpha and HIF-3alpha, whereas HIF-1alpha only interacted with HDAC7 in the class II HDAC family. Although HDAC7 was localized dominantly in the cytoplasm at normal oxygen concentrations, HDAC7 co-translocated to the nucleus with HIF-1alpha under hypoxic conditions. In the nucleus, HDAC7 increased transcriptional activity of HIF-1alpha through the formation of a complex with HIF-1alpha, HDAC7, and p300. Taken together, these results indicate that HDAC7 is a novel transcriptional activator of HIF-1alpha
Kato
Hiroyuki
H
Department of Molecular Cell Physiology, Tokyo Metropolitan Institute of Medical Science, 3-18-22 Honkomagome, Bunkyo-ku, Tokyo 113-8613, Japan. h-kato@rinshoken.or.jp
Tamamizu-Kato
Shiori
S
Shibasaki
Futoshi
F
D000123:Acetyltransferases / Q000378:metabolism; D021581:Active Transport, Cell Nucleus; D000818:Animals; D018797:Cell Cycle Proteins / Q000378:metabolism; D051272:Glucose Transporter Type 1; D051548:Histone Acetyltransferases; D006655:Histone Deacetylases / Q000378:metabolism* / Q000502:physiology; D006801:Humans; D000860:Hypoxia / Q000235:genetics*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009004:Monosaccharide Transport Proteins / Q000235:genetics; D011485:Protein Binding; D051381:Rats; D012097:Repressor Proteins; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor
D000123:Acetyltransferases; D018797:Cell Cycle Proteins; D051272:Glucose Transporter Type 1; D051548:Histone Acetyltransferases; D006655:Histone Deacetylases; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009004:Monosaccharide Transport Proteins; D012097:Repressor Proteins; D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor; C497442:HIF1A protein, human; C495677:SLC2A1 protein, human; C400300:HDAC4 protein, human; C404500:HDAC5 protein, human; C543273:HDAC7 protein, human; C498619:Hdac5 protein, rat