HYPOXIA-INDUCED TRANSCRIPTIONAL ACTIVATION AND INCREASED MESSENGER-RNA STABILITY OF VASCULAR ENDOTHELIAL GROWTH-FACTOR IN C6 GLIOMA-CELLS
HYPOXIA-INDUCED TRANSCRIPTIONAL ACTIVATION AND INCREASED MESSENGER-RNA STABILITY OF VASCULAR ENDOTHELIAL GROWTH-FACTOR IN C6 GLIOMA-CELLS
复制标题
DOI：
10.1074/jbc.270.34.19761
复制
发表时间：
1995-08-25
影响因子：
4.8
通讯作者：
RISAU, W
中科院分区：
文献类型：
--
作者：
IKEDA, E;ACHEN, MG;RISAU, W
血管内皮生长因子（VEGF）是一种内皮特异性的促血管生成的有丝分裂原，由包括肿瘤细胞在内的多种细胞分泌。越来越多的证据表明，VEGF是生理和病理性血管生成的主要调节因子，并且VEGF/VEGF受体系统已被证明是胶质瘤血管生成所必需的。缺氧似乎在胶质瘤进展过程中诱导VEGF表达中起关键作用，C6胶质瘤细胞为研究肿瘤血管生成提供了体内胶质瘤模型，并且体外研究表明缺氧上调C6细胞中VEGF的表达。然而，关于低氧诱导VEGF的分子机制知之甚少。在这里，我们表明，缺氧诱导C6细胞中的VEGF是由于转录激活和mRNA的稳定性增加。核运行的分析表明，一个快速和持久的转录激活，而mRNA半衰期的测定表明，在缺氧过程中的mRNA稳定性增加较慢。报告基因的研究表明，在VEGF基因的5 '侧翼区存在低氧应答的转录激活元件。这些结果表明，低氧诱导的基因表达涉及多种不同的分子机制，并以双相方式被激活。
Vascular endothelial growth factor (VEGF) is an endothelial specific angiogenic mitogen secreted from various cell types including tumor cells. Increasing evidence suggests that VEGF is a major regulator of physiological and pathological angiogenesis, and the VEGF/VEGF receptor system has been shown to be necessary for glioma angiogenesis. Hypoxia seems to play a critical role in the induction of VEGF expression during glioma progression, C6 glioma cells provide an in vivo glioma model for the study of tumor angiogenesis, and the expression of VEGF in C6 cells has been shown to be up regulated by hypoxia in vitro. However, little is known about the molecular mechanism of hypoxic induction of VEGF. Here, we demonstrate that hypoxic induction of VEGF in C6 cells is due to both transcriptional activation and increased stability of mRNA. Nuclear run-on assays revealed a fast and lasting transcriptional activation, whereas the determination of mRNA half-life showed a slower increase of mRNA stability during hypoxia. Reporter gene studies revealed that hypoxia responsive transcription-activating elements were present in the 5'-flanking region of the VEGF gene, These results suggested that several distinct molecular mechanisms were involved in hypoxia-induced gene expression and were activated in a biphasic manner.