Delta-1 activation of notch-1 signaling results in HES-1 transactivation
Delta-1 activation of notch-1 signaling results in HES-1 transactivation
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DOI：
10.1128/mcb.18.12.7423
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发表时间：
1998-12-01
影响因子：
5.3
通讯作者：
Israël, A
中科院分区：
文献类型：
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作者：
Jarriault, S;Le Bail, O;Israël, A
Notch受体参与了许多脊椎动物和无脊椎动物的细胞命运决定事件。研究表明，在果蝇中，delta依赖的Notch信号激活了无毛的转录因子抑制因子，导致分裂基因增强子的表达增加。遗传证据也暗示了kuzbanian基因，它编码一种分解金属蛋白酶，在Notch信号通路中。通过双细胞共培养实验，我们发现脊椎动物Dl-1激活Notch-1级联。与先前获得的数据一致，随着Notch-1的活性形式，hes -1衍生的启动子结构在表达Notch-1的细胞中响应Dl-1刺激被反激活。破坏全长受体的蛋白水解成熟导致HES-1反活化的减少，进一步支持了只有成熟加工的Notch才在细胞表面表达并被其配体激活的假设。此外，我们观察到Dl-1诱导的HES-1转录激活依赖于Kuzbanian和RBP-J活性，这与这两种蛋白在果蝇Notch信号传导中的参与一致。我们还观察到，Notch-1表达细胞暴露于Dl-1导致内源性HES-1 mRNA水平升高。最后，表达dl -1的细胞与肌源性C2细胞共培养抑制了C2细胞向肌管的分化，正如之前Jagged-1和Jagged-2所证明的那样，并且还导致内源性HES-1 mRNA水平升高。因此，Dl-1作为Notch-1的功能性配体，具有与Jagged蛋白相同的抑制细胞分化的能力。
The Notch receptor is involved in many cell fate determination events in vertebrates and invertebrates. It has been shown in Drosophila melanogaster that Delta-dependent Notch signaling activates the transcription factor Suppressor of Hairless, leading to an increased expression of the Enhancer of Split genes. Genetic evidence has also implicated the kuzbanian gene, which encodes a disintegrin metalloprotease, in the Notch signaling pathway. By using a two-cell coculture assay, we show here that vertebrate Dl-1 activates the Notch-1 cascade. Consistent with previous data obtained,vith active forms of Notch-1 a HES-1-derived promoter construct is transactivated in cells expressing Notch-1 in response to Dl-1 stimulation. Impairing the proteolytic maturation of the full-length receptor leads to a decrease in HES-1 transactivation, further supporting the hypothesis that only mature processed Notch is expressed at the cell surface and activated by its ligand. Furthermore, we observed that Dl-1-induced HES-1 transactivation was dependent both on Kuzbanian and RBP-J activities, consistent with the involvement of these two proteins in Notch signaling in Drosophila, We also observed that exposure of Notch-1-expressing cells to Dl-1 results in an increased level of endogenous HES-1 mRNA. Finally, coculture of Dl-1-expressing cells with myogenic C2 cells suppresses differentiation of C2 cells into myotubes, as previously demonstrated for Jagged-1 and Jagged-2, and also leads to an increased level of endogenous HES-1 mRNA. Thus, Dl-1 behaves as a functional ligand for Notch-1 and has the same ability to suppress cell differentiation as the Jagged proteins do.