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Notch signaling regulates the FOXP3 promoter through RBP-J- and Hes1-dependent mechanisms

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Abstract

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.

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Abbreviations

RBP-J:

Recombination signal binding protein-Jk

NIC:

Intracellular domain of Notch

Treg:

Regulatory T-cells

Hes:

Hairy and enhancer of split

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Acknowledgments

We thank Ms Hui Wang for her critical correction of English during the preparation of the manuscript. The study was supported by grants from the National Natural Science Foundation of China (30570804, 30330550, 30425015, and 30400079) and the Ministry of Science and Technology of China (2006AA02A111), and by the PCSIRT project of the Ministry of Education of China.

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Authors and Affiliations

  1. Department of Respiratory Diseases, Xijing Hospital, Fourth Military Medical University, Xi’an, 710032, China

    Hai-Feng Ou-Yang, Chang-Gui Wu, Xin-Yu Ti, Li-Qiang Song, Hao-Wen Qi & Hua Han

  2. State Key Laboratory of Cancer Biology, Department of Medical Genetics and Developmental Biology, Fourth Military Medical University, Xi’an, 710032, China

    Hong-Wei Zhang, Ping Zhang, Jian Zhang, Jun-Chang Li, Li-Hong Hou, Fei He, Su-Zhen Zhang, Lei Feng & Hua Han

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  1. Hai-Feng Ou-Yang
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  2. Hong-Wei Zhang
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  9. Xin-Yu Ti
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  14. Hua Han
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Correspondence to Hua Han.

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Hai-Feng Ou-Yang, Hong-Wei Zhang, Chang-Gui Wu and Jian Zhang contributed equally to this study.

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Ou-Yang, HF., Zhang, HW., Wu, CG. et al. Notch signaling regulates the FOXP3 promoter through RBP-J- and Hes1-dependent mechanisms. Mol Cell Biochem 320, 109–114 (2009). https://doi.org/10.1007/s11010-008-9912-4

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  • DOI: https://doi.org/10.1007/s11010-008-9912-4

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