Activator-protein-1 binding potentiates the hypoxia-inducible factor-1-mediated hypoxia-induced transcriptional activation of vascular-endothelial growth factor expression in C6 glioma cells
Activator-protein-1 binding potentiates the hypoxia-inducible factor-1-mediated hypoxia-induced transcriptional activation of vascular-endothelial growth factor expression in C6 glioma cells
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DOI：
10.1042/bj3270419
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发表时间：
1997-10-15
影响因子：
4.1
通讯作者：
Risau, W
中科院分区：
文献类型：
--
作者：
Damert, A;Ikeda, E;Risau, W
内皮细胞特异性丝裂原血管内皮生长因子（VEGF）在生理性和病理性血管生成中都起着关键作用。在氧张力降低的情况下，VEGF表达上调是通过转录和转录后机制发生的。为了研究缺氧（1%氧气）转录激活的分子机制，在C6胶质瘤细胞中使用荧光素酶报告基因构建物对人VEGF启动子的缺氧反应区域进行了精细定位。在这里，我们报道了缺氧诱导因子1 （HIF1）的结合位点对于缺氧诱导VEGF基因表达至关重要。然而，含有HIF1结合位点的增强子亚片段并不足以产生完全的缺氧反应。上游序列的加入恢复了对缺氧诱导的完全敏感性。这种增强作用是由于激活蛋白1的结合。“增强”序列本身不能赋予缺氧反应性。我们的研究结果强烈表明，在C6胶质瘤细胞中，一系列复杂的反式作用因子促进了缺氧对VEGF基因表达的完全转录诱导。
The endothelial cell-specific mitogen vascular-endothelial growth factor (VEGF) plays a key role in both physiological and pathological angiogenesis. The up-regulation of VEGF expression in response to reduced oxygen tension occurs through transcriptional and post-transcriptional mechanisms. To investigate the molecular mechanisms of transcriptional activation by hypoxia (1% oxygen), fine mapping of a hypoxia-responsive region of the human VEGF promoter was carried out using luciferase reporter-gene constructs in C6 glioma cells. Here, we report that the binding site of hypoxia-inducible factor 1 (HIF1) is crucial for the hypoxic induction of VEGF gene expression. However, an enhancer subfragment containing the HIF1 binding site was not sufficient to confer full hypoxia responsiveness. Addition of upstream sequences restored the full sensitivity to hypoxia induction. This potentiating effect is due to activator protein 1 binding. The 'potentiating' sequences are unable to confer hypoxia responsiveness on their own. Our results strongly suggest that in C6 glioma cells a complex array of trans-acting factors facilitates full transcriptional induction of VEGF gene expression by hypoxia.