Notch 1 and 3 receptors modulate vascular smooth muscle cell growth, apoptosis and migration via a CBF-1/RBP-Jk dependent pathway
Notch 1 and 3 receptors modulate vascular smooth muscle cell growth, apoptosis and migration via a CBF-1/RBP-Jk dependent pathway
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DOI：
10.1096/fj.04-1700fje
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发表时间：
2004-07-01
期刊：
影响因子：
4.8
通讯作者：
Cahill, PA
中科院分区：
文献类型：
--
作者：
Sweeney, C;Morrow, D;Cahill, PA
血管平滑肌细胞（SMC）的命运决定（细胞生长、迁移和凋亡）是血管疾病发病机制的基本特征。我们研究了Notch 1和3受体信号传导在体外控制成人SMC命运中的作用，通过建立分裂的毛状增强子（hes-1和-5）和相关的hrt（hrt-1，-2和-3）是SMC中Notch 1和3受体的直接下游靶基因，并确定了核蛋白CBF-1/RBP-Jk在其调节中的重要作用。活性Notch 1和3受体（Notch IC）的组成型表达导致CBF-1/RBP-Jk依赖性启动子活性和Notch靶基因表达的显著上调，伴随着SMC生长的显著增加，同时抑制SMC凋亡和迁移。此外，用CBF-1的非DNA结合突变体、缺失其Δ RAM结构域的Notch IC和Epstein-Barr病毒编码的RPMS-1以及Notch IC受体运输的药理学抑制剂（布雷菲德菌素A和莫能菌素）抑制内源性Notch介导的CBF-1/RBP-Jk调节的基因表达，导致细胞生长显著降低，同时伴随增加SMC凋亡和迁移。这些发现表明内源性Notch受体和下游靶基因控制体外血管细胞命运。因此，Notch信号转导代表了一种新的治疗靶点，用于体内血管细胞命运发生变化的疾病状态。
Vascular smooth muscle cell (SMC) fate decisions ( cell growth, migration, and apoptosis) are fundamental features in the pathogenesis of vascular disease. We investigated the role of Notch 1 and 3 receptor signaling in controlling adult SMC fate in vitro by establishing that hairy enhancer of split (hes-1 and -5) and related hrt's (hrt-1, -2, and -3) are direct downstream target genes of Notch 1 and 3 receptors in SMC and identified an essential role for nuclear protein CBF-1/RBP-Jk in their regulation. Constitutive expression of active Notch 1 and 3 receptors (Notch IC) resulted in a significant up-regulation of CBF-1/RBP-Jk-dependent promoter activity and Notch target gene expression concomitant with significant increases in SMC growth while concurrently inhibiting SMC apoptosis and migration. Moreover, inhibition of endogenous Notch mediated CBF-1/RBP-Jk regulated gene expression with a non-DNA binding mutant of CBF-1, a Notch IC deleted of its delta RAM domain and the Epstein-Barr virus encoded RPMS-1, in conjunction with pharmacological inhibitors of Notch IC receptor trafficking ( brefeldin A and monensin), resulted in a significant decrease in cell growth while concomitantly increasing SMC apoptosis and migration. These findings suggest that endogenous Notch receptors and downstream target genes control vascular cell fate in vitro. Notch signaling, therefore, represents a novel therapeutic target for disease states in which changes in vascular cell fate occur in vivo.