HIF-1α, STAT3, CBP/p300 and Ref-1/APE are components of a transcriptional complexthat regulates Src-dependent hypoxia-induced expression of VEGF in pancreatic and prostate carcinomas
HIF-1α, STAT3, CBP/p300 and Ref-1/APE are components of a transcriptional complexthat regulates Src-dependent hypoxia-induced expression of VEGF in pancreatic and prostate carcinomas
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DOI：
10.1038/sj.onc.1208513
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发表时间：
2005-04-28
期刊：
影响因子：
8
通讯作者：
Gallick, GE
中科院分区：
文献类型：
--
作者：
Gray, MJ;Zhang, J;Gallick, GE
缺氧刺激许多对癌细胞存活至关重要的途径，包括血管内皮生长因子（VEGF）转录的激活。在正常的成纤维细胞中，缺氧诱导的蛋白酪氨酸激酶Src的活化是VEGF表达所必需的。我们在胰腺癌和前列腺癌细胞系中发现，氯化钴（用于模拟缺氧）诱导的VEGF表达需要Src激活，并导致HIF-1 α稳态水平升高，信号和转录转导子3（STAT 3）磷酸化水平升高。STAT 3和缺氧诱导因子（HIF）-1 α同时结合VEGF启动子，在那里它们与转录辅激活因子CBP/p300和Ref-1/APE形成分子复合物。从诱导型启动子表达活化的Src足以增加VEGF表达并形成这些含STAT 3/HIF-1 α的启动子复合物。通过表达STAT 3或HIF-1 α显性负突变体抑制DNA结合显著降低VEGF表达。这些数据表明，STAT 3和HIF-1 α与VEGF启动子的结合是缺氧后VEGF mRNA最大转录所需的。
Hypoxia stimulates a number of pathways critical to cancer cell survival, including the activation of vascular endothelial growth factor ( VEGF) transcription. In normal fibroblasts, hypoxia-induced activation of the protein tyrosine kinase, Src, is required for VEGF expression. We show here in both pancreatic and prostate carcinoma cell lines cobalt chloride ( used to mimic hypoxia) - induced VEGF expression requires Src activation and leads to increased steady-state levels of HIF-1 alpha and increased phosphorylation of signal and transducer of transcription 3 (STAT3). STAT3 and hypoxia-inducible factor (HIF)-1 alpha bind simultaneously to the VEGF promoter, where they form a molecular complex with the transcription coactivators CBP/p300 and Ref-1/APE. Expression of activated Src from an inducible promoter is sufficient to increase VEGF expression and form these STAT3/HIF-1 alpha-containing promoter complexes. Inhibition of DNA binding by expression of either STAT3 or HIF-1 alpha dominant negative mutants significantly reduces VEGF expression. These data suggest that the binding of both STAT3 and HIF-1 alpha to the VEGF promoter is required for maximum transcription of VEGF mRNA following hypoxia.