Synthetic transactivation screening reveals ETV4 as broad coactivator of hypoxia-inducible factor signaling.
Synthetic transactivation screening reveals ETV4 as broad coactivator of hypoxia-inducible factor signaling.
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DOI：
10.1093/nar/gkr978
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发表时间：
2012-03
影响因子：
14.9
通讯作者：
Stiehl DP
中科院分区：
文献类型：
--
作者：
Wollenick K;Hu J;Kristiansen G;Schraml P;Rehrauer H;Berchner-Pfannschmidt U;Fandrey J;Wenger RH;Stiehl DP
人脯氨酰-4-羟化酶结构域（PHD）蛋白1-3被称为细胞氧传感器，通过降解缺氧诱导因子（HIF）α亚基起作用。PHD 2和PHD 3基因是由HIF本身诱导的，这表明涉及PHD丰度的负反馈回路。为了鉴定PHD 2基因的新调节子，通过允许区分HIF依赖性和HIF非依赖性启动子调节的方法筛选704个转录因子的表达阵列。其中，E-twenty six转录因子ETS易位变体4（ETV 4）被发现有助于PHD 2基因表达，特别是在缺氧条件下。通过哺乳动物双杂交和荧光共振能量转移分析，观察到ETV 4和HIF-1/2α之间形成复合物的机制。HIF-1α结构域定位、CITED 2过表达和HIF抑制因子耗竭实验为HIF-1α和p300/CBP在ETV 4结合中的协同作用提供了证据。染色质免疫沉淀证实ETV 4和HIF-1α共募集到PHD 2启动子。在通过全基因组表达谱发现的608个缺氧诱导的转录物中，7.7%需要ETV 4进行有效的缺氧诱导，这表明ETV 4在缺氧基因调控中具有广泛的作用。在282例人乳腺癌组织样本中，内源性ETV 4与PHD 2、HIF-1/2α和几种已建立的组织缺氧标志物高度相关，证实了ETV 4和HIF途径之间的功能性相互作用。
The human prolyl-4-hydroxylase domain (PHD) proteins 1–3 are known as cellular oxygen sensors, acting via the degradation of hypoxia-inducible factor (HIF) α-subunits. PHD2 and PHD3 genes are inducible by HIFs themselves, suggesting a negative feedback loop that involves PHD abundance. To identify novel regulators of the PHD2 gene, an expression array of 704 transcription factors was screened by a method that allows distinguishing between HIF-dependent and HIF-independent promoter regulation. Among others, the E-twenty six transcription factor ETS translocation variant 4 (ETV4) was found to contribute to PHD2 gene expression particularly under hypoxic conditions. Mechanistically, complex formation between ETV4 and HIF-1/2α was observed by mammalian two-hybrid and fluorescence resonance energy transfer analysis. HIF-1α domain mapping, CITED2 overexpression and factor inhibiting HIF depletion experiments provided evidence for cooperation between HIF-1α and p300/CBP in ETV4 binding. Chromatin immunoprecipitation confirmed ETV4 and HIF-1α corecruitment to the PHD2 promoter. Of 608 hypoxically induced transcripts found by genome-wide expression profiling, 7.7% required ETV4 for efficient hypoxic induction, suggesting a broad role of ETV4 in hypoxic gene regulation. Endogenous ETV4 highly correlated with PHD2, HIF-1/2α and several established markers of tissue hypoxia in 282 human breast cancer tissue samples, corroborating a functional interplay between the ETV4 and HIF pathways.
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DOI：
10.1073/pnas.93.23.12969
发表时间：
1996-11-12
影响因子：
11.1
作者：
Arany, Z;Huang, LE;Livingston, DM
通讯作者：
Livingston, DM
影响因子：
8
作者：
Bordoli, M. R.;Stiehl, D. P.;Camenisch, G.
通讯作者：
Camenisch, G.
影响因子：
4.8
作者：
Liu, YM;Borchert, GL;Phang, JM
通讯作者：
Phang, JM
影响因子：
7.7
作者：
Loenarz, Christoph;Coleman, Mathew L.;Schofield, Christopher J.
通讯作者：
Schofield, Christopher J.
DOI：
10.1073/pnas.0705680105
发表时间：
2008-03-25
影响因子：
11.1
作者：
Ginouves, Amandine;Ilc, Karine;Berra, Edurne
通讯作者：
Berra, Edurne