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首页> 外文期刊>American Journal of Physiology >CD40-induced transcriptional activation of vascular endothelial growth factor involves a 68-bp region of the promoter containing a CpG island.
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CD40-induced transcriptional activation of vascular endothelial growth factor involves a 68-bp region of the promoter containing a CpG island.

机译：CD40诱导的血管内皮生长因子的转录激活涉及包含CpG岛的启动子的68 bp区域。

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Vascular endothelial growth factor (VEGF) is produced by several cell types in the kidney, and its expression is tightly regulated for the maintenance of normal renal physiology. Increases or decreases in its expression are associated with proteinuria and renal disease. Recently, we found that the expression of VEGF is markedly induced following interactions between CD40 ligand (CD40L) and CD40. Here, endothelial cells (EC) or Jurkat T cell lines were transiently transfected with luciferase reporter constructs under the control of the human VEGF promoter and were treated with human soluble CD40L (sCD40L). We identified a CD40-responsive 68-bp region (bp -50 to +18) of the promoter and 43 bp within this region (bp -25 to +18) that have 97% homology to a sequence of CpG dinucleotides. A computerized search revealed that the CpG region has putative binding domains for the transcriptional repressor protein methyl CpG binding protein-2 (MeCP2). In EMSA, we found that the 43-bp methylated sequence formed four complex(es) with nuclear extracts from untreated EC and reduced binding of at least one complex when nuclear lysates from sCD40L-activated EC (30 min) were used. Supershift analysis using anti-MeCP2 demonstrated that most of the complex(es) in both untreated and sCD40L-activated EC involved interactions between the 43-bp DNA and MeCP2. In addition, we found that other CpG binding proteins may also interact with this region of the promoter. Taken together, this is the first demonstration that CpG binding transcriptional repressor proteins including MeCP2 may be of importance in VEGF biology.
机译：血管内皮生长因子（VEGF）由肾脏中的几种细胞类型产生，并且其表达受到严格调节以维持正常的肾脏生理。其表达的增加或减少与蛋白尿和肾脏疾病有关。最近，我们发现在CD40配体（CD40L）和CD40之间相互作用后，VEGF的表达被明显诱导。在此，在人VEGF启动子的控制下用荧光素酶报道基因构建体瞬时转染内皮细胞（EC）或Jurkat T细胞系，并用人可溶性CD40L（sCD40L）处理。我们确定了启动子的CD40响应68 bp区域（bp -50至+18）和该区域内的43 bp（bp -25至+18），与CpG二核苷酸序列具有97％的同源性。计算机搜索显示，CpG区具有转录抑制蛋白甲基CpG结合蛋白2（MeCP2）的推定结合结构域。在EMSA中，我们发现，使用sCD40L激活的EC（30分钟）的核裂解液时，该43 bp的甲基化序列与未经处理的EC的核提取物形成了四个复合物，并降低了至少一种复合物的结合。使用抗MeCP2的超位移分析表明，未处理的和sCD40L激活的EC中的大多数复合物都涉及43 bp DNA与MeCP2之间的相互作用。此外，我们发现其他CpG结合蛋白也可能与启动子的这一区域相互作用。综上所述，这是第一个证明包括MeCP2在内的CpG结合转录阻遏蛋白在VEGF生物学中的重要性。

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