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首页> 外文期刊>Molecular and Cellular Biology >A Single-Nucleotide Polymorphism in a Half-Binding Site Creates p53 and Estrogen Receptor Control of Vascular Endothelial Growth Factor Receptor 1
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A Single-Nucleotide Polymorphism in a Half-Binding Site Creates p53 and Estrogen Receptor Control of Vascular Endothelial Growth Factor Receptor 1

机译：在一个半结合位点的单核苷酸多态性创建血管内皮生长因子受体1的p53和雌激素受体控制。

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Interactions between master regulatory pathways provide higher-order controls for cellular regulation. Recently, we reported a C→T single-nucleotide polymorphism (SNP) in the vascular endothelial growth factor receptor 1 (VEGFR-1/Flt1) promoter that merges human VEGF and p53 pathways. This finding suggested a new layer in environmental controls of a pathway relevant to several diseases. The Flt1-T SNP created what appeared to be a half-site p53 target response element (RE). The absence of information about p53 gene responsiveness mediated by half-site REs led us to address how it influences Flt1 expression. We now identify a second regulatory sequence comprising a partial RE for estrogen receptors (ERs) upstream of the p53 binding site. Surprisingly, this provides for synergistic stimulation of transcription specifically at the Flt1-T allele through the combined action of ligand-bound ER and stress-induced p53. In addition to demonstrating direct control of Flt1 expression by ER and p53 proteins acting as sequence-specific transcription factors at half-site REs, we establish a new interaction between three master regulatory pathways, p53, ER, and VEGF. The mechanism of joint regulation through half-sites is likely relevant to transcriptional control of other targets and expands the number of genes that may be directly controlled in master regulatory networks.
机译：主调节途径之间的相互作用为细胞调节提供了更高层次的控制。最近，我们报道了融合人类VEGF和p53途径的血管内皮生长因子受体1（VEGFR-1 / Flt1）启动子中的C→T单核苷酸多态性（SNP）。这一发现表明环境控制中与几种疾病有关的途径有了新的发展。 Flt1-T SNP产生了一个似乎是半位点的p53目标反应元件（RE）。缺乏有关由半位REs介导的p53基因反应性的信息，导致我们研究了它如何影响Flt1表达。现在我们鉴定出第二种调控序列，该序列包含p53结合位点上游的部分雌激素受体（ERs）的RE。令人惊讶地，这通过配体结合的ER和应激诱导的p53的联合作用提供了协同刺激，特别是在Flt1-T等位基因处的转录。除了证明通过ER和在半位点REs上作为序列特异性转录因子的p53蛋白直接控制Flt1表达外，我们还在p53，ER和VEGF这三个主要调控途径之间建立了新的相互作用。通过半位点进行联合调控的机制可能与其他靶标的转录控制有关，并扩大了在主调控网络中可能直接控制的基因数量。

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