PTB-associated splicing factor inhibits IGF-1-induced VEGF upregulation in a mouse model of oxygen-induced retinopathy
PTB-associated splicing factor inhibits IGF-1-induced VEGF upregulation in a mouse model of oxygen-induced retinopathy
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PTB 相关剪接因子抑制氧诱导视网膜病变小鼠模型中 IGF-1 诱导的 VEGF 上调
DOI：
10.1007/s00441-014-2104-5
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发表时间：
2015-05-01
影响因子：
3.6
通讯作者：
Li, Xiaorong
中科院分区：
文献类型：
--
作者：
Dong, Lijie;Nian, Hong;Li, Xiaorong
病理性视网膜新生血管，包括早产儿视网膜病变和年龄相关性黄斑变性，是世界范围内最常见的致盲原因。胰岛素样生长因子-1（IGF-1）对内皮细胞具有直接的促有丝分裂作用，是血管生成的基础。血管内皮生长因子（VEGF）激活响应IGF-1是有据可查的，但是，负责终止IGF-1信号的分子机制仍然没有完全阐明。在这里，我们表明，多聚嘧啶束结合蛋白相关剪接因子（PSF）是一个潜在的负调节VEGF的表达诱导IGF刺激。功能分析表明，异位表达的PSF抑制IGF-1刺激的转录激活和VEGF基因的mRNA表达，而敲低PSF增加IGF-1刺激的反应。PSF将Hakai招募到VEGF转录复合物中，导致IGF-1介导的转录抑制。Hakai siRNA转染逆转了PSF介导的VEGF基因转录抑制。总之，这些结果表明，PSF可以通过募集Hakai复合物来抑制IGF-1刺激的VEGF的转录激活，并描绘了一种新的IGF-1/VEGF信号传导的调节机制，该机制可能在眼部疾病中的新血管形成的发病机制中具有意义。
Pathological retinal neovascularization, including retinopathy of prematurity and age-related macular degeneration, is the most common cause of blindness worldwide. Insulin-like growth factor-1 (IGF-1) has a direct mitogenic effect on endothelial cells, which is the basis of angiogenesis. Vascular endothelial growth factor (VEGF) activation in response to IGF-1 is well documented; however, the molecular mechanisms responsible for the termination of IGF-1 signaling are still not completely elucidated. Here, we show that the polypyrimidine tract-binding protein-associated splicing factor (PSF) is a potential negative regulator of VEGF expression induced by IGF stimulation. Functional analysis demonstrated that ectopic expression of PSF inhibits IGF-1-stimulated transcriptional activation and mRNA expression of the VEGF gene, whereas knockdown of PSF increased IGF-1-stimulated responses. PSF recruited Hakai to the VEGF transcription complex, resulting in inhibition of IGF-1-mediated transcription. Transfection with Hakai siRNA reversed the PSF-mediated transcriptional repression of VEGF gene transcription. In summary, these results show that PSF can repress the transcriptional activation of VEGF stimulated by IGF-1 via recruitment of the Hakai complex and delineate a novel regulatory mechanism of IGF-1/VEGF signaling that may have implications in the pathogenesis of neovascularization in ocular diseases.