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题名: Tet1 facilitates hypoxia tolerance by stabilizing the HIF-alpha proteins independent of its methylcytosine dioxygenase activity
作者: Wang, Jing1; Zhang, Dawei1; Du, Juan1; Zhou, Chi1; Li, Zhi1; Liu, Xing1; Ouyang, Gang1; Xiao, Wuhan1, 2, 3
刊名: NUCLEIC ACIDS RESEARCH
发表日期: 2017-12-15
DOI: 10.1093/nar/gkx869
卷: 45, 期:22
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: Because of the requirement of oxygen (O-2) to produce energy, aerobic organisms developed mechanisms to protect themselves against a shortage of oxygen in both acute status and chronic status. To date, how organisms tolerate acute hypoxia and the underlying mechanisms remain largely unknown. Here, we identify that Tet1, one member of the ten-eleven translocation (TET) family of methylcytosine dioxygenases, is required for hypoxia tolerance in zebrafish and mice. Tet1-null zebrafish and mice are more sensitive to hypoxic conditions compared with their wild-type siblings. We demonstrate that Tet1 stabilizes hypoxia-inducible factor alpha (HIF-alpha) and enhances HIF-alpha transcription activity independent of its enzymatic activity. In addition, we show that Tet1 modulates HIF-2 alpha and HIF-1 alpha through different mechanisms. Tet1 competes with prolyl hydroxylase protein 2 (PHD2) to bind to HIF-2 alpha, resulting in a reduction of HIF-2 alpha hydroxylation by PHD2. For HIF1 alpha, however, Tet1 has no effect on HIF-1 alpha hydroxylation, but rather it appears to stabilize the C-terminus of HIF-1 alpha by affecting lysine site modification. Furthermore, we found that Tet1 enhances rather than prevents poly-ubiquitination on HIF-alpha. Our results reveal a previously unrecognized function of Tet1 independent of its methylcytosine dioxygenase activity in hypoxia signaling.
关键词[WOS]: HIGH-ALTITUDE ADAPTATION ; HIPPEL-LINDAU PROTEIN ; INDUCIBLE FACTORS ; DNA DEMETHYLATION ; DEGRADATION ; TIBETAN ; CANCER ; METHYLATION ; HIF-1-ALPHA ; PHD2
语种: 英语
项目资助者: Chinese Academy of Sciences(XDA08010208) ; NSFC(31461163003 ; 91631102 ; 31601051 ; 31671315 ; 31721005)
WOS记录号: WOS:000419064400015
ISSN号: 0305-1048
Citation statistics:
内容类型: 期刊论文
URI标识: http://ir.ihb.ac.cn/handle/342005/43678
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, State Key Lab Freshwater Ecol & Biotechnol, Inst Hydrobiol, Wuhan 430072, Hubei, Peoples R China
2.Chinese Acad Sci, Key Lab Aquat Biodivers & Conservat, Inst Hydrobiol, Wuhan 430072, Hubei, Peoples R China
3.Minist Agr, Key Lab Aquaculture Dis Control, Wuhan 430072, Hubei, Peoples R China
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