Physical and functional interaction of Runt-related protein 1 with hypoxia-inducible factor-1α
Physical and functional interaction of Runt-related protein 1 with hypoxia-inducible factor-1α
复制标题
DOI：
10.1038/sj.onc.1210676
复制
发表时间：
2008-01-31
期刊：
影响因子：
8
通讯作者：
Chen, G. Q.
中科院分区：
文献类型：
--
作者：
Peng, Z. G.;Zhou, M. Y.;Chen, G. Q.
血管生成和造血密切相关，相互作用，但很少有研究，以确定血管生成促进蛋白和造血相关转录因子之间的可能联系。在这里，我们研究了血管生成相关缺氧诱导因子-1 α（HIF-1 α）的氧敏感α亚基与Runt相关蛋白1（Runx 1，也称为急性髓性白血病-1，AML-1）的潜在关系，Runx 1是一种重要的造血转录因子。结果表明，Runx 1与HIF-1 α蛋白之间存在一定程度的直接相互作用，其中Runx 1的Runt同源结构域主要参与其中。白血病相关的异常Runx 1融合蛋白AML 1-ETO，其将Runx 1蛋白的N-末端177个氨基酸残基与ETO（8 - 21 - 1）蛋白在读框内融合，也与HIF-1 α蛋白相互作用，其能力比Runx 1本身更强。更有趣的是，Runx 1过表达抑制HIF-1蛋白的DNA结合和转录活性，降低HIF-1靶向基因（如血管内皮生长因子）的表达，而特异性小干扰RNA沉默Runx 1表达显著增加HIF-1蛋白的转录活性，表明Runx 1抑制HIF-1的转录依赖性功能。反之亦然，HIF-1 α增加DNA结合能力和Runx 1蛋白的转录活性。所有这些数据将为理解Runx 1和HIF-1 α相关的造血细胞分化和血管生成提供新的见解。
Angiogenesis and hematopoiesis are closely linked and interactive with each other, but few studies were given to identify possible links between angiogenesis-promoting proteins and hematopoiesis-related transcription factors. Here we investigated the potential relationship of oxygen-sensitive alpha-subunit of angiogenesis-related hypoxia-inducible factor-1 alpha (HIF-1 alpha) with Runt-related protein 1 (Runx1, also known as acute myeloid leukemia-1, AML-1), an important hematopoietic transcription factor. The results demonstrated that Runx1 and HIF-1 alpha proteins directly interacted with each other to a degree, in which Runt homology domain of Runx1 was mainly involved. Leukemia-related abnormal Runx1 fusion protein AML1-ETO, which fuses the N-terminal 177 amino acid residues of the Runx1 protein in frame to ETO (eight-twenty-one) protein, also interacted with HIF-1 alpha protein with greater ability than Runx1 itself. More intriguingly, Runx1 overexpression inhibited DNA-binding and transcriptional activity of HIF-1 protein with reduced expression of HIF-1-targeted genes such as vascular endothelial growth factor, while silence of Runx1 expression by specific small interfering RNA significantly increased transcriptional activity of HIF-1 protein, suggesting that Runx1 inhibited transcription-dependent function of HIF-1. Vice versa, HIF-1 alpha increased DNA-binding ability and transcriptional activity of Runx1 protein. All these data would shed new insight to understanding Runx1 and HIF-1 alpha-related hematopoietic cell differentiation and angiogenesis.