TNF induction of jagged-1 in endothelial cells is NFkappaB-dependent.
TNF induction of jagged-1 in endothelial cells is NFkappaB-dependent.
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DOI：
10.1016/j.gene.2009.01.003
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发表时间：
2009-04-15
期刊：
影响因子：
3.5
通讯作者：
Hughes CC
中科院分区：
文献类型：
--
作者：
Johnston DA;Dong B;Hughes CC
TNF-α是一种诱导内皮细胞（EC）粘附分子的强效促炎细胞因子。此外，TNF通过诱导EC尖端细胞表型和缺口途径的配体jagged-1的表达来促进血管生成。Notch信号传导对于血管形成至关重要，并有助于限制尖端细胞的增殖。在这里，我们证明，在人类EC的锯齿状-1的TNF诱导是快速的，并依赖于通过TNFR 1，但不是TNFR 2的信号。携带3.7 kb人基因5′启动子序列的荧光素酶报告基因构建体对TNF和NFκB途径组分的过表达都有反应。用NFκB抑制剂或显性阴性IKKβ共表达阻断TNF诱导的启动子激活。在一个假定的NFκ B结合位点-3.0 kb处的突变，在多个物种中是保守的，导致对TNF和NFκB的反应性丧失。电迁移率变化和染色质免疫沉淀试验显示，结合p50和p65的启动子在响应TNF治疗。完整的启动子活性也依赖于-2.0 kb处的AP-1位点。这些结果表明，经典的NFκB信号转导是TNF诱导EC中notch配体jagged-1所必需的。
TNF-α is a potent proinflammatory cytokine that induces endothelial cell (EC) adhesion molecules. In addition, TNF promotes angiogenesis by inducing an EC tip cell phenotype and the expression of jagged-1, a ligand for the notch pathway. Notch signaling is critical for vascular patterning and helps to restrict the proliferation of tip cells. Here we demonstrate that TNF induction of jagged-1 in human EC is rapid and dependent upon signaling through TNFR1, but not TNFR2. A luciferase reporter construct carrying 3.7 kb of 5′ promoter sequence from the human gene was responsive to both TNF and overexpression of NFκB pathway components. TNF-induced promoter activation was blocked by treatment with an NFκB inhibitor or co-expression of dominant-negative IKKβ. Mutations in a putative NFκB-binding site at −3.0 kb, which is conserved across multiple species, resulted in a loss of responsiveness to TNF and NFκB. Electromobility shift and chromatin immunoprecipitation assays revealed binding of both p50 and p65 to the promoter in response to TNF treatment. Full promoter activity also depends on an AP-1 site at −2.0 kb. These results indicate that canonical NFκB signaling is required for TNF induction of the notch ligand jagged-1 in EC.
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DOI：
10.1073/pnas.0709663105
发表时间：
2008-02-12
影响因子：
11.1
作者：
High, Frances A.;Lu, Min Min;Epstein, Jonathan A.
通讯作者：
Epstein, Jonathan A.
影响因子：
4.8
作者：
Sainson, RCA;Aoto, J;Hughes, CCW
通讯作者：
Hughes, CCW
影响因子：
5.3
作者：
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通讯作者：
Verma, IM
DOI：
10.1073/pnas.0611177104
发表时间：
2007-02-27
影响因子：
11.1
作者：
Suchting, Steven;Freitas, Catarina;Eichmann, Anne
通讯作者：
Eichmann, Anne
影响因子：
6
作者：
Lindner, V;Booth, C;Liaw, L
通讯作者：
Liaw, L