STAT3 or USF2 contributes to HIF target gene specificity.
STAT3 or USF2 contributes to HIF target gene specificity.
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DOI：
10.1371/journal.pone.0072358
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Hu CJ
中科院分区：
文献类型：
--
作者：
Pawlus MR;Wang L;Murakami A;Dai G;Hu CJ
HIF 1和HIF 2介导的转录反应在实体瘤进展中起关键作用。尽管有显著的相似性，包括它们与HIF 1和HIF 2靶基因的启动子的结合，但HIF 1和HIF 2蛋白在缺氧条件下激活靶基因的独特子集。HIF靶基因特异性的机制仍不清楚。使用siRNA或抑制剂，我们以前报道过STAT 3或USF 2是激活内源性HIF 1或HIF 2靶基因所必需的。在这项研究中，使用报告基因分析和染色质免疫沉淀，我们发现，STAT 3或USF 2表现出特异性结合HIF 1或HIF 2靶基因的启动子分别即使在过表达。在功能上，HIF 1 α与STAT 3相互作用，以HIF 1 α HLH/PAS和N-Arg依赖性方式激活HIF 1靶基因启动子，而HIF 2 α与USF 2相互作用，以HIF 2 α N-Arg依赖性方式激活HIF 2靶基因启动子。物理上，HIF 1 α HLH和PAS结构域是其与STAT 3相互作用所必需的，而HIF 2 α的N-和C-TADs都参与与USF 2的物理相互作用。重要的是，将功能性USF 2结合位点添加到HIF 1靶基因启动子中增加了启动子的基础活性以及其对HIF 2 + USF 2活化的响应，而用来自HIF 2靶基因的HBS替换HIF结合位点不改变报告基因的特异性。重要的是，HIF 1或HIF 2靶基因上的RNA Pol II主要以STAT 3或USF 2依赖性方式与HIF 1 α或HIF 2 α相关。因此，我们首次证明HIF靶基因特异性是通过HIF靶基因激活所需的HIF转录伴侣实现的，它们与HIF 1或HIF 2靶基因的启动子特异性结合，并选择性地与HIF 1 α或HIF 2 α蛋白相互作用。
The HIF1- and HIF2-mediated transcriptional responses play critical roles in solid tumor progression. Despite significant similarities, including their binding to promoters of both HIF1 and HIF2 target genes, HIF1 and HIF2 proteins activate unique subsets of target genes under hypoxia. The mechanism for HIF target gene specificity has remained unclear. Using siRNA or inhibitor, we previously reported that STAT3 or USF2 is specifically required for activation of endogenous HIF1 or HIF2 target genes. In this study, using reporter gene assays and chromatin immuno-precipitation, we find that STAT3 or USF2 exhibits specific binding to the promoters of HIF1 or HIF2 target genes respectively even when over-expressed. Functionally, HIF1α interacts with STAT3 to activate HIF1 target gene promoters in a HIF1α HLH/PAS and N-TAD dependent manner while HIF2α interacts with USF2 to activate HIF2 target gene promoters in a HIF2α N-TAD dependent manner. Physically, HIF1α HLH and PAS domains are required for its interaction with STAT3 while both N- and C-TADs of HIF2α are involved in physical interaction with USF2. Importantly, addition of functional USF2 binding sites into a HIF1 target gene promoter increases the basal activity of the promoter as well as its response to HIF2+USF2 activation while replacing HIF binding site with HBS from a HIF2 target gene does not change the specificity of the reporter gene. Importantly, RNA Pol II on HIF1 or HIF2 target genes is primarily associated with HIF1α or HIF2α in a STAT3 or USF2 dependent manner. Thus, we demonstrate here for the first time that HIF target gene specificity is achieved by HIF transcription partners that are required for HIF target gene activation, exhibit specific binding to the promoters of HIF1 or HIF2 target genes and selectively interact with HIF1α or HIF2α protein.
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DOI：
10.1074/jbc.m901790200
发表时间：
2009-06-19
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Mole DR;Blancher C;Copley RR;Pollard PJ;Gleadle JM;Ragoussis J;Ratcliffe PJ
通讯作者：
Ratcliffe PJ
影响因子：
11.2
作者：
Aprelikova, Olga;Wood, Matthew;Barrett, J. Carl
通讯作者：
Barrett, J. Carl
影响因子：
5.3
作者：
Alfranca, A;Gutiérrez, MD;Landázuri, MO
通讯作者：
Landázuri, MO
影响因子：
11.4
作者：
Kim, William Y.;Safran, Michal;Kaelin, William G., Jr.
通讯作者：
Kaelin, William G., Jr.
影响因子：
4.8
作者：
Elvert, G;Kappel, A;Flamme, I
通讯作者：
Flamme, I