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题名: Forkhead Transcription Factor 3a (FOXO3a) Modulates Hypoxia Signaling via Up-regulation of the von Hippel-Lindau Gene (VHL)
作者: Liu, Xing1; Cai, Xiaolian1; Hu, Bo1; Mei, Zhichao1; Zhang, Dawei1; Ouyang, Gang1; Wang, Jing1; Zhang, Wei1; Xiao, Wuhan1, 2
关键词: FOXO ; hypoxia ; hypoxia-inducible factor (HIF) ; stress ; transcription regulation ; zebrafish ; pVHL
刊名: JOURNAL OF BIOLOGICAL CHEMISTRY
发表日期: 2016-12-02
DOI: 10.1074/jbc.M116.745471
卷: 291, 期:49, 页:25692-25705
收录类别: SCI
文章类型: Article
WOS标题词: Science & Technology ; Life Sciences & Biomedicine
类目[WOS]: Biochemistry & Molecular Biology
研究领域[WOS]: Biochemistry & Molecular Biology
英文摘要: 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 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.
关键词[WOS]: HIGH-ALTITUDE ADAPTATION ; CELL RENAL-CARCINOMA ; OXIDATIVE STRESS ; HIF-ALPHA ; PROTEASOMAL DEGRADATION ; INDUCIBLE FACTORS ; BETA-CATENIN ; PVHL ; PROTEIN ; PATHWAY
语种: 英语
项目资助者: National Natural Science Foundation in China (NSFC)(31401072) ; Chinese Academy of Sciences Major Scientific and Technological Project(XDA08010208) ; NSFC(31461163003 ; 91631102 ; 31671315)
WOS记录号: WOS:000390095300034
ISSN号: 0021-9258
Citation statistics:
内容类型: 期刊论文
URI标识: http://ir.ihb.ac.cn/handle/342005/28771
Appears in Collections:水生生物分子与细胞生物学研究中心_期刊论文

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作者单位: 1.Chinese Acad Sci, Key Lab Aquat Biodivers & Conservat, Inst Hydrobiol, Wuhan 430072, Peoples R China
2.Chinese Acad Sci, Inst Hydrobiol, State Key Lab Freshwater Ecol & Biotechnol, Wuhan 430072, Peoples R China
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