Vascular endothelial growth factor receptor-2 - Counter-regulation by the transcription factors, TFII-I AND TFII-IRD1
Vascular endothelial growth factor receptor-2 - Counter-regulation by the transcription factors, TFII-I AND TFII-IRD1
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DOI：
10.1074/jbc.m500335200
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发表时间：
2005-08-19
影响因子：
4.8
通讯作者：
Danoff, SK
中科院分区：
文献类型：
--
作者：
Jackson, TA;Taylor, HE;Danoff, SK
血管内皮生长因子受体-2（VEGFR-2/KDR/flk-1）是内皮细胞中血管内皮生长因子活化的主要介质。VEGFR-2表达的调节在有丝分裂、分化和血管生成中似乎是关键的。VEGFR-2的转录调控是复杂的，可能涉及多个推定的上游调控元件，包括E盒。转录起始依赖于转录起始位点侧翼的起始（Inr）元件。转录因子TFII-I以Inr依赖的方式增强VEGFR-2的转录。TFII-I在结构和功能上都不寻常。TFII-I转录因子家族成员含有多个推定的DNA结合结构域。在功能上，TFII-I作用于基础Inr元件以及几个不同的上游调控位点。据推测，TFII-I的结构可能允许与给定启动子中的基础位点和调节位点同时相互作用。由于已知TFII-I作用于调控位点，包括E盒以及基础Inr元件，我们评估了不依赖Inr的TFII-I激活VEGFR-2启动子的可能性。我们发现Inr突变的VEGFR-2报告基因构建体保留了TFII-I刺激的活性。我们证明了TFII-I结合到人VEGFR-2启动子中的Inr和三个调节E盒。此外，siRNA降低TFII-I表达导致VEGFR-2表达降低。我们还描述了TFII-IRD 1对VEGFR-2启动子的反调节。我们发现TFII-I能够在一个启动子的基础和调节位点起作用，并且人VEGFR-2启动子在功能上受TFII-I和TFII-IRD 1的反调节。
The vascular endothelial growth factor receptor-2 (VEGFR-2/KDR/flk-1) functions as the primary mediator of vascular endothelial growth factor activation in endothelial cells. Regulation of VEGFR-2 expression appears critical in mitogenesis, differentiation, and angiogenesis. Transcriptional regulation of the VEGFR-2 is complex and may involve multiple putative upstream regulatory elements including E boxes. Transcript initiation is dependent on an initiator (Inr) element flanking the transcriptional start site. The transcription factor, TFII-I, enhances VEGFR-2 transcription in an Inr-dependent fashion. TFII-I is unusual both structurally and functionally. The TFII-I transcription factor family members contain multiple putative DNA binding domains. Functionally, TFII-I acts at both the basal, Inr element as well as at several distinct upstream regulatory sites. It has been postulated that the structure of TFII- I might allow simultaneous interaction with both basal and regulatory sites in a given promoter. As TFII-I is known to act at regulatory sites including E boxes as well as at the basal Inr element, we evaluated the possibility of Inr-independent TFII- I activation of the VEGFR-2 promoter. We found that an Inr-mutated VEGFR-2 reporter construct retains TFII-I-stimulated activity. We demonstrated that TFII-I binds to both the Inr and to three regulatory E boxes in the human VEGFR-2 promoter. In addition, reduction in TFII- I expression by siRNA results in decreased VEGFR-2 expression. We also describe counter-regulation of the VEGFR-2 promoter by TFII-IRD1. We found that TFII-I is capable of acting at both basal and regulatory sites in one promoter and that the human VEGFR-2 promoter is functionally counter-regulated by TFII-I and TFII-IRD1.