Notch signaling regulates the FOXP3 promoter through RBP-J- and Hes1-dependent mechanisms
Notch signaling regulates the FOXP3 promoter through RBP-J- and Hes1-dependent mechanisms
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DOI：
10.1007/s11010-008-9912-4
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发表时间：
2009-01-01
影响因子：
4.3
通讯作者：
Han, Hua
中科院分区：
文献类型：
--
作者：
Ou-Yang, Hai-Feng;Zhang, Hong-Wei;Han, Hua
有证据表明，Notch信号转导调节CD 4（+）CD 25（+）调节性T细胞（T细胞）。由于转录因子Foxp 3是调控TGFAP发育和功能的主要分子，因此我们研究了Notch信号是否可能直接调控Foxp 3的表达。在这里，我们提供的证据表明，Notch信号可以通过RBP-J和Hes 1依赖性机制调节FOXP 3启动子。一个保守的RBP-J结合位点和N-box位点内的FOXP 3启动子进行了鉴定。我们表明，Notch细胞内结构域（NIC），Notch受体的活性形式，激活FOXP 3启动子驱动的报告。FOXP 3启动子的解剖揭示了RBP-J结合位点和N盒的双重作用：RBP-J结合位点正向调节FOXP 3启动子活性，而N盒负向调节FOXP 3启动子活性。此外，在新鲜分离的TcB中，NIC-RBP-J复合物结合到TcB中的FOXP 3启动子。我们的研究结果表明，Notch信号可能通过调节Foxp 3的表达参与了TcB的发育和功能。
Evidence has shown that Notch signaling modulates CD4(+)CD25(+) regulatory T-cells (Tregs). As transcription factor Foxp3 acts as a master molecule governing the development and function of Tregs, we investigated whether Notch signaling might directly regulate Foxp3 expression. Here, we provide evidence that Notch signaling can modulate the FOXP3 promoter through RBP-J- and Hes1-dependent mechanisms. A conserved RBP-J-binding site and N-box sites were identified within the FOXP3 promoter. We show that the Notch intracellular domain (NIC), the active form of Notch receptors, activates a reporter driven by the FOXP3 promoter. Dissection of the FOXP3 promoter revealed bipartite effects of the RBP-J-binding site and the N-boxes: the RBP-J-binding site positively, while the N-boxes negatively regulated the FOXP3 promoter activity. Moreover, in freshly isolated Tregs, NIC-RBP-J complex is bound to the FOXP3 promoter in Tregs. Our results suggest that Notch signaling might be involved in the development and function of Tregs through regulating Foxp3 expression.