Runx1 promotes angiogenesis by downregulation of insulin-like growth factor-binding protein-3
Runx1 promotes angiogenesis by downregulation of insulin-like growth factor-binding protein-3
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DOI：
10.1038/sj.onc.1208287
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发表时间：
2005-02-10
期刊：
影响因子：
8
通讯作者：
Hara, T
中科院分区：
文献类型：
--
作者：
Iwatsuki, K;Tanaka, K;Hara, T
缺乏RUNX1转录因子的小鼠胚胎表现出血管生成缺陷，并伴有造血干细胞(HSCs)的缺失。为了研究RUNX1是否在血管生成中起直接作用，我们从RUNX1缺失小鼠的腹主动脉-性腺-中肾(AGM)区域建立了一种新的内皮祖细胞系，命名为AEL-DeltaR1。我们在多西环素诱导启动子的作用下，将RUNX1基因导入AEL-DeltaR1细胞。恢复表达RUNX1后，AEL-DeltaR1细胞在Matrigel上形成血管网络的能力显著增强。通过比较RUNX1诱导前后AEL-DeltaR1细胞中的mRNAs，我们发现RUNX1下调了胰岛素样生长因子结合蛋白3(IGFBP-3)的mRNA表达。凝胶滞留和报告实验表明，RUNX1与小鼠IGFBP-3基因的启动子区域结合并抑制其转录。在Matrigel实验中外源性加入IGFBP-3后，RUNX1的促血管生成活性被抑制，且呈剂量依赖关系。这些结果表明，RUNX1通过抑制IGFBP-3mRNA的表达直接参与血管生成。
Mouse embryos lacking the Runx1 transcription factor exhibit an angiogenic defect accompanied by the absence of hematopoietic stem cells ( HSCs). To ask whether Runx1 plays a direct role in angiogenesis, we established a novel endothelial progenitor cell line, designated AEL-DeltaR1, from the aorta-gonad-mesonephros ( AGM) region of Runx1-null mouse. We introduced Runx1 cDNA into AEL-DeltaR1 cells under the doxycycline-inducible promoter. The ability of AEL-DeltaR1 cells to form vascular networks on matrigel was highly enhanced by the restored expression of Runx1. By molecular comparison of mRNAs in AEL-DeltaR1 cells before and after the induction of Runx1, we found that mRNA expression of insulin-like growth factor-binding protein 3 (IGFBP-3) is downregulated by Runx1. Gel retardation and reporter assays revealed that Runx1 binds to the promoter region of mouse IGFBP-3 gene and represses its transcription. When IGFBP-3 was exogenously added in the matrigel assay, the angiogenesis-enhancing activity of Runx1 was suppressed in a dose-dependent manner. These results demonstrate that Runx1 is directly involved in angiogenesis by repression of IGFBP-3 mRNA expression.