Integration of Notch 1 and Calcineurin/NFAT signaling pathways in keratinocyte growth and differentiation control
Integration of Notch 1 and Calcineurin/NFAT signaling pathways in keratinocyte growth and differentiation control
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DOI：
10.1016/j.devcel.2005.02.016
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发表时间：
2005-05-01
影响因子：
11.8
通讯作者：
Dotto, GP
中科院分区：
文献类型：
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作者：
Mammucari, C;di Vignano, AT;Dotto, GP
Notch 和钙调神经磷酸酶/NFAT 通路均与角质形成细胞分化的控制有关。在分化的角质形成细胞中，Notch 1 激活对 p21(WAF1/Cip1) 基因的诱导与 RBP-J kappa 蛋白直接靶向 p21 启动子有关。我们在此表明，Notch 1 激活还通过作用于 p21 TATA 盒近端区域的第二种钙调神经磷酸酶依赖性机制发挥作用。 Notch 信号传导增加的钙调磷酸酶/NFAT 活性涉及通过 HES-1 依赖性机制下调钙加压素（一种内源性钙调磷酸酶抑制剂）。除了控制 p21 基因外，钙调神经磷酸酶还对角质形成细胞对 Notch 1 激活的转录反应做出显着贡献，无论是体外还是体内。事实上，皮肤中钙调神经磷酸酶 B1 基因的缺失会导致周期性脱发表型，这与涉及毛囊结构和/或与周围间质粘附的 Notch 反应基因的表达改变有关。因此，Notch 1 和钙调神经磷酸酶-NFAT 通路在角质形成细胞生长/分化控制中存在重要的相互联系。
The Notch and Calcineurin/NFAT pathways have both been implicated in control of keratinocyte differentiation. Induction of the p21(WAF1/Cip1) gene by Notch 1 activation in differentiating keratinocytes is associated with direct targeting of the RBP-J kappa protein to the p21 promoter. We show here that Notch 1 activation functions also through a second Calcineurin-dependent mechanism acting on the p21 TATA box-proximal region. Increased Calcineurin/NFAT activity by Notch signaling involves downregulation of Calcipressin, an endogenous Calcineurin inhibitor, through a HES-1-dependent mechanism. Besides control of the p21 gene, Calcineurin contributes significantly to the transcriptional response of keratinocytes to Notch 1 activation, both in vitro and in vivo. In fact, deletion of the Calcineurin B1 gene in the skin results in a cyclic alopecia phenotype, associated with altered expression of Notch-responsive genes involved in hair follicle structure and/or adhesion to the surrounding mesenchyme. Thus, an important interconnection exists between Notch 1 and Calcineurin-NFAT pathways in keratinocyte growth/differentiation control.