ZFIN ID: ZDB-PUB-161026-9
Forkhead transcription factor 3a (FOXO3a) modulates hypoxia signaling via up-regulation of von Hippel-Lindau gene (VHL)
Liu, X., Cai, X., Hu, B., Mei, Z., Zhang, D., Ouyang, G., Wang, J., Zhang, W., Xiao, W.
Date: 2016
Source: The Journal of biological chemistry   291(49): 25692-25705 (Journal)
Registered Authors: Hu, Bo, Mei, Zhichao, Ouyang, Gang, Wang, Jing, Xiao, Wuhan, Zhang, Wei
Keywords: FOXO, hypoxia, hypoxia-inducible factor (HIF), pVHL, stress, transcription regulation, zebrafish
MeSH Terms:
  • Animals
  • Cell Hypoxia
  • Forkhead Box Protein O3/genetics
  • Forkhead Box Protein O3/metabolism*
  • HEK293 Cells
  • Humans
  • Response Elements*
  • Signal Transduction*
  • Tumor Suppressor Proteins/biosynthesis*
  • Tumor Suppressor Proteins/genetics
  • Up-Regulation*
  • Von Hippel-Lindau Tumor Suppressor Protein/biosynthesis*
  • Von Hippel-Lindau Tumor Suppressor Protein/genetics
  • Zebrafish/genetics
  • Zebrafish/metabolism*
  • Zebrafish Proteins/biosynthesis*
  • Zebrafish Proteins/genetics
PubMed: 27777301 Full text @ J. Biol. Chem.
FOXO3a, a member of the forkhead homeobox type O (FOXO) family of transcriptional factors, regulates cell survival in response to DNA damage, caloric restriction, and oxidative stress. The von Hippel-Lindau (VHL) tumor suppressor gene encodes a component of the E3 ubiquitin ligase complex that mediates hypoxia-inducible factor-α (HIF-α) degradation under aerobic conditions, thus acting as one of the key regulators of hypoxia signaling. However, whether FOXO3a impacts cellular hypoxia stress remains unknown. Herein, we show that FOXO3a directly binds to VHL promoter and up-regulates VHL expression. Using a zebrafish model, we confirmed the up-regulation of vhl by foxo3b, an orthologue of mammalian FOXO3a. Furthermore, by employing the CRISPR/Cas9 technology, we deleted foxo3b in zebrafish and determined that expression of hypoxia-inducible genes was affected under hypoxia. Moreover, foxo3b-null zebrafish exhibited impaired acute hypoxic tolerance, resulting in death. In conclusion, our findings suggest that by modulating HIF activity via up-regulation of VHL, FOXO3a (foxo3b) plays an important role in survival in response to hypoxic stress.