ASB4 is a Hydroxylation substrate of FIH and promotes vascular differentiation via an oxygen-dependent mechanism
ASB4 is a Hydroxylation substrate of FIH and promotes vascular differentiation via an oxygen-dependent mechanism
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DOI：
10.1128/mcb.00511-07
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发表时间：
2007-09-01
影响因子：
5.3
通讯作者：
Patterson, Cam
中科院分区：
文献类型：
--
作者：
Ferguson, James E., III;Wu, Yaxu;Patterson, Cam
内皮细胞分化为功能性血管网络的分子机制尚未完全了解。为了鉴定内皮发育中的新因素，我们使用了分化胚胎干细胞（ES）的微阵列筛选，该筛选鉴定了锚蛋白重复序列和SOCS盒蛋白4（ASB 4）的基因，作为早期分化过程中血管谱系中最高度差异表达的基因。与其他含SOCS盒的蛋白质一样，ASB 4是延伸蛋白B/延伸蛋白C/cullin/ Roe泛素连接酶复合物的底物识别分子，其介导底物蛋白的泛素化和降解。胚胎血管系统中高水平的ASB 4表达与胎盘血液开始时氧张力的急剧增加相一致。然而，随着血管成熟和氧水平稳定，ASB 4表达迅速下调，表明ASB 4可能起调节内皮特异性反应以增加氧张力的作用。与ASB 4功能受氧浓度调节的假设一致，ASB 4与抑制HIF 1 α（FIH）的因子相互作用，并且是通过氧依赖性机制的FIH介导的羟基化的底物。此外，ES细胞中ASB 4的过表达以氧依赖性方式促进向血管谱系的分化。我们推测ASB 4在常氧下的羟基化促进底物蛋白的结合和降解以调节血管分化。
The molecular mechanisms of endothelial differentiation into a functional vascular network are incompletely understood. To identify novel factors in endothelial development, we used a microarray screen with differentiating embryonic stem (ES) cells that identified the gene for ankyrin repeat and SOCS box protein 4 (ASB4) as the most highly differentially expressed gene in the vascular lineage during early differentiation. Like other SOCS box-containing proteins, ASB4 is the substrate recognition molecule of an elongin B/elongin C/cullin/ Roe ubiquitin ligase complex that mediates the ubiquitination and degradation of substrate protein(s). High levels of ASB4 expression in the embryonic vasculature coincide with drastic increases in oxygen tension as placental blood How is initiated. However, as vessels mature and oxygen levels stabilize, ASB4 expression is quickly downregulated, suggesting that ASB4 may function to modulate an endothelium-specific response to increasing oxygen tension. Consistent with the hypothesis that ASB4 function is regulated by oxygen concentration, ASB4 interacts with the factor inhibiting HIF1 alpha (FIH) and is a substrate for FIH-mediated hydroxylation via an oxygen-dependent mechanism. Additionally, overexpression of ASB4 in ES cells promotes differentiation into the vascular lineage in an oxygen-dependent manner. We postulate that hydroxylation of ASB4 in normoxia promotes binding to and degradation of substrate protein(s) to modulate vascular differentiation.