Nuclear factor of activated T cells balances angiogenesis activation and inhibition.
Nuclear factor of activated T cells balances angiogenesis activation and inhibition.
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活化T细胞的核因子平衡血管生成激活和抑制。
DOI：
10.1084/jem.20040474
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发表时间：
2004-06-07
影响因子：
15.3
通讯作者：
Volpert, OV
中科院分区：
文献类型：
--
作者：
Zaichuk, TA;Shroff, EH;Emmanuel, R;Filleur, S;Nelius, T;Volpert, OV
关键词：
已经证明，血管内皮细胞生长因子（VEGF）诱导血管生成需要活化T细胞核因子（NFAT）的活化。我们发现，NFATc 2也被碱性成纤维细胞生长因子激活，并被血管生成色素上皮衍生因子（PEDF）抑制剂阻断。这表明该转录因子在调节血管生成中作为刺激和抑制信号之间的汇聚点的关键作用。我们确定c-Jun NH 2-末端激酶（JNKs）作为血管生成中NFAT活性的重要上游调节因子。我们区分了JNK-2负责PEDF和JNK-1和JNK-2作为PEDF驱动的NFAT核输出的介质的NFATc 2细胞质保留。我们发现了一个新的NFAT靶点，caspase-8抑制剂细胞Fas相关死亡结构域样白细胞介素1β转换酶抑制蛋白（c-FLIP），其表达受VEGF和PEDF的共同调节。染色质免疫沉淀显示，VEGF依赖性增加NFATc 2结合c-FLIP启动子在体内，这是减弱PEDF。我们提出，一个可能的机制，协同血管生成的调节激活剂和抑制剂可能是调制的内皮细胞凋亡，通过c-FLIP控制的NFAT及其上游调控JNK。
It has been demonstrated that vascular endothelial cell growth factor (VEGF) induction of angiogenesis requires activation of the nuclear factor of activated T cells (NFAT). We show that NFATc2 is also activated by basic fibroblast growth factor and blocked by the inhibitor of angiogenesis pigment epithelial–derived factor (PEDF). This suggests a pivotal role for this transcription factor as a convergence point between stimulatory and inhibitory signals in the regulation of angiogenesis. We identified c-Jun NH2-terminal kinases (JNKs) as essential upstream regulators of NFAT activity in angiogenesis. We distinguished JNK-2 as responsible for NFATc2 cytoplasmic retention by PEDF and JNK-1 and JNK-2 as mediators of PEDF-driven NFAT nuclear export. We identified a novel NFAT target, caspase-8 inhibitor cellular Fas-associated death domain–like interleukin 1β–converting enzyme inhibitory protein (c-FLIP), whose expression was coregulated by VEGF and PEDF. Chromatin immunoprecipitation showed VEGF-dependent increase of NFATc2 binding to the c-FLIP promoter in vivo, which was attenuated by PEDF. We propose that one possible mechanism of concerted angiogenesis regulation by activators and inhibitors may be modulation of the endothelial cell apoptosis via c-FLIP controlled by NFAT and its upstream regulator JNK.
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影响因子：
4.8
作者：
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通讯作者：
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影响因子：
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