Notch activation induces endothelial cell cycle arrest and participates in contact inhibition:: Role of p21Cip1 repression
Notch activation induces endothelial cell cycle arrest and participates in contact inhibition:: Role of p21Cip1 repression
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DOI：
10.1128/mcb.24.20.8813-8822.2004
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发表时间：
2004-10-01
影响因子：
5.3
通讯作者：
Karsan, A
中科院分区：
文献类型：
--
作者：
Noseda, M;Chang, L;Karsan, A
虽然先前的研究表明，在血管生成和血管稳态过程中需要适当的Notch信号，但Notch调节血管功能的机制仍有待阐明。本研究表明，配体Jagged1激活Notch通路可减少内皮细胞的增殖。Notch激活通过抑制视网膜母细胞瘤蛋白（Rb）的磷酸化，以细胞自主的方式抑制内皮细胞的增殖。在细胞周期进入期间，内皮细胞中的p21（Cip1）上调。激活的Notch抑制丝裂原诱导的p21（Cip1）上调，并延迟细胞周期蛋白d -cdk4介导的Rb磷酸化。缺口依赖的p21（Cip1）抑制阻止细胞周期蛋白D和cdk4的核定位。通过RNA干扰靶向下调p21(Cip1)，证实了p21（Cip1）在细胞周期蛋白D-cdk4核转运和内皮细胞s期进入中的必要性。我们进一步证明，当内皮细胞到达汇合时，Notch被激活，p21（Cip1）下调。在汇合处抑制Notch通路可阻止p21（Cip1）下调并诱导Rb磷酸化。我们认为Notch激活有助于内皮细胞的接触抑制，部分是通过抑制p21（Cip1）的表达。
Although previous studies demonstrate that appropriate Notch signaling is required during angiogenesis and in vascular homeostasis, the mechanisms by which Notch regulates vascular function remain to be elucidated. Here, we show that activation of the Notch pathway by the ligand Jagged1 reduces the proliferation of endothelial cells. Notch activation inhibits proliferation of endothelial cells in a cell-autonomous manner by inhibiting phosphorylation of the retinoblastoma protein (Rb). During cell cycle entry, p21(Cip1) is upregulated in endothelial cells. Activated Notch inhibits mitogen-induced upregulation of p21(Cip1) and delays cyclin D-cdk4-mediated Rb phosphorylation. Notch-dependent repression of p21(Cip1) prevents nuclear localization of cyclin D and cdk4. The necessity of p21(Cip1) for nuclear translocation of cyclin D-cdk4 and S-phase entry in endothelial cells was demonstrated by targeted downregulation of p21(Cip1) by using RNA interference. We further demonstrate that when endothelial cells reach confluence, Notch is activated and p21(Cip1) is downregulated. Inhibition of the Notch pathway at confluence prevents p21(Cip1) downregulation and induces Rb phosphorylation. We suggest that Notch activation contributes to contact inhibition of endothelial cells, in part through repression of p21(Cip1) expression.