title: 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: From the Key Laboratory of Aquatic Biodiversity and Conservation and.
authors: Xing
authors: X
authors: Liu
authors: From the Key Laboratory of Aquatic Biodiversity and Conservation and.
authors: Xiaolian
authors: X
authors: Cai
authors: From the Key Laboratory of Aquatic Biodiversity and Conservation and.
authors: Bo
authors: B
authors: Hu
authors: From the Key Laboratory of Aquatic Biodiversity and Conservation and.
authors: Zhichao
authors: Z
authors: Mei
authors: From the Key Laboratory of Aquatic Biodiversity and Conservation and.
authors: Dawei
authors: D
authors: Zhang
authors: From the Key Laboratory of Aquatic Biodiversity and Conservation and.
authors: Gang
authors: G
authors: Ouyang
authors: From the Key Laboratory of Aquatic Biodiversity and Conservation and.
authors: Jing
authors: J
authors: Wang
authors: From the Key Laboratory of Aquatic Biodiversity and Conservation and.
authors: Wei
authors: W
authors: Zhang
authors: From the Key Laboratory of Aquatic Biodiversity and Conservation and w-xiao@ihb.ac.cn.|State Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan 430072, China.
authors: Wuhan
authors: W
authors: Xiao
mesh_terms: D000818:Animals; D015687:Cell Hypoxia; D000071316:Forkhead Box Protein O3 / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D020218:Response Elements; D015398:Signal Transduction; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis* / Q000235:genetics; D015854:Up-Regulation; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000096:biosynthesis* / Q000235:genetics; D015027:Zebrafish / Q000235:genetics / Q000378:metabolism*; D029961:Zebrafish Proteins / Q000096:biosynthesis* / Q000235:genetics
chemical_list: C499517:FOXO3 protein, human; D000071316:Forkhead Box Protein O3; D025521:Tumor Suppressor Proteins; C542158:Vhl protein, zebrafish; D029961:Zebrafish Proteins; D051794:Von Hippel-Lindau Tumor Suppressor Protein; C497446:VHL protein, human
keywords: FOXO; hypoxia; hypoxia-inducible factor (HIF); pVHL; stress; transcription regulation; zebrafish