Forkhead Transcription Factor 3a (FOXO3a) Modulates Hypoxia Signaling via Up-regulation of the von Hippel-Lindau Gene (VHL).

Abstract

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 degradation under aerobic conditions, thus acting as one of the key regulators of hypoxia signaling. However, whether FOXO3a impacts cellular hypoxia stress remains unknown. Here we show that FOXO3a directly binds to the VHL promoter and up-regulates VHL expression. Using a zebrafish model, we confirmed the up-regulation of vhl by foxo3b, an ortholog of mammalian FOXO3a Furthermore, by employing the clustered regularly interspaced short palindromic repeats (CRISPR)-associated RNA-guided endonuclease Cas9 (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 hypoxia-inducible factor activity via up-regulation of VHL, FOXO3a (foxo3b) plays an important role in survival in response to hypoxic stress.

• Authors: Xing Liu, Xiaolian Cai, Bo Hu, Zhichao Mei, Dawei Zhang, Gang Ouyang, Jing Wang, Wei Zhang, Wuhan Xiao
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 291 Issue 49 Pg. 25692-25705 (Dec 02 2016) ISSN: 1083-351X [Electronic] United States
• PMID: 27777301 (Publication Type: Journal Article)
• Copyright: © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

Chemical References

• FOXO3 protein, human
• Forkhead Box Protein O3
• Tumor Suppressor Proteins
• Vhl protein, zebrafish
• Zebrafish Proteins
• Von Hippel-Lindau Tumor Suppressor Protein
• VHL protein, human

Topics

• Animals
• Cell Hypoxia
• Forkhead Box Protein O3 (genetics, metabolism)
• HEK293 Cells
• Humans
• Response Elements
• Signal Transduction
• Tumor Suppressor Proteins (biosynthesis, genetics)
• Up-Regulation
• Von Hippel-Lindau Tumor Suppressor Protein (biosynthesis, genetics)
• Zebrafish (genetics, metabolism)
• Zebrafish Proteins (biosynthesis, genetics)