VEGFR2 translocates to the nucleus to regulate its own transcription.
VEGFR2 translocates to the nucleus to regulate its own transcription.
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DOI：
10.1371/journal.pone.0025668
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Santos SC
中科院分区：
文献类型：
--
作者：
Domingues I;Rino J;Demmers JA;de Lanerolle P;Santos SC
血管内皮生长因子受体-2（VEGFR 2）是VEGF血管生成作用的主要介质。除了其作为激活多种信号传导途径的膜受体的众所周知的作用之外，VEGFR 2还具有核定位。然而，VEGFR 2在细胞核中的作用仍然未知。在本报告中，我们表明，在内皮细胞中，核VEGFR 2与几个核蛋白，包括Sp1，一个转录因子，已牵连在血管生成所需的基因的调节相互作用。通过体内染色质免疫沉淀（ChIP）测定，我们发现VEGFR 2结合到VEGFR 2近端启动子的Sp1响应区。使用VEGFR 2启动子的相同区域，通过EMSA测定证实了这些结果。重要的是，我们表明VEGFR 2 DNA结合直接与VEGFR 2启动子的转录激活有关。通过报告基因分析，我们发现相对于转录起始位点的-300/-116之间的区域对于赋予VEGFR 2依赖性转录活性是必需的。先前描述了VEGFR 2的核转位依赖于其被VEGF激活。一致地，我们观察到VEGFR 2与DNA的结合需要VEGF活化，这被贝伐单抗和舒尼替尼阻断，贝伐单抗和舒尼替尼是两种抑制VEGFR 2活化的抗血管生成剂。我们的研究结果证明了VEGFR 2激活其自身启动子的新机制，该启动子可能参与放大血管生成反应。
Vascular Endothelial Growth Factor Receptor-2 (VEGFR2) is the major mediator of the angiogenic effects of VEGF. In addition to its well known role as a membrane receptor that activates multiple signaling pathways, VEGFR2 also has a nuclear localization. However, what VEGFR2 does in the nucleus is still unknown. In the present report we show that, in endothelial cells, nuclear VEGFR2 interacts with several nuclear proteins, including the Sp1, a transcription factor that has been implicated in the regulation of genes needed for angiogenesis. By in vivo chromatin immunoprecipitation (ChIP) assays, we found that VEGFR2 binds to the Sp1-responsive region of the VEGFR2 proximal promoter. These results were confirmed by EMSA assays, using the same region of the VEGFR2 promoter. Importantly, we show that the VEGFR2 DNA binding is directly linked to the transcriptional activation of the VEGFR2 promoter. By reporter assays, we found that the region between -300/-116 relative to the transcription start site is essential to confer VEGFR2-dependent transcriptional activity. It was previously described that nuclear translocation of the VEGFR2 is dependent on its activation by VEGF. In agreement, we observed that the binding of VEGFR2 to DNA requires VEGF activation, being blocked by Bevacizumab and Sunitinib, two anti-angiogenic agents that inhibit VEGFR2 activation. Our findings demonstrate a new mechanism by which VEGFR2 activates its own promoter that could be involved in amplifying the angiogenic response.
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影响因子：
7.8
作者：
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