Notch-4 / Int3的ANK重复序列在不存在Rbpj的情况下激活NF-κB的经典途径，并引起乳腺肿瘤的发生。,Scientific Reports

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Notch-4 / Int3的ANK重复序列在不存在Rbpj的情况下激活NF-κB的经典途径，并引起乳腺肿瘤的发生。
Scientific Reports ( IF 3.8 ) Pub Date : 2017-Oct-20 , DOI: 10.1038/s41598-017-13989-7
Ahmed Raafat , Sharon Bargo , David McCurdy , Robert Callahan

在乳腺中表达Notch-4细胞内结构域（指定为Int3）的转基因小鼠具有两种表型表现出100％的渗透性：乳腺肺泡/小叶发育的停滞和乳腺肿瘤的发生。Notch-4信号转导主要是通过Int3与转录抑制子/激活子Rbpj的相互作用来介导的。有趣的是，WAP-Int3 / Rbpj敲除小鼠的乳腺发育正常，但仍发育成乳腺肿瘤，其潜伏期比WAP-Int3小鼠稍长。因此，Notch诱导的乳腺肿瘤的发展是Rbpj独立的。在这里，我们显示Int3通过与IKK信号小体缔合，在不存在Rbpj的情况下激活HC11细胞中的NF-κB。Int3诱导HC11细胞中的经典NF-κB活性和P50磷酸化，而没有改变NF-κB2途径。激活NF-κB所需的Int3蛋白中的最小结构域由CDC10 /锚蛋白（ANK）重复结构域组成。用IKK抑制剂治疗携带WAP-Int3肿瘤的小鼠会导致肿瘤消退。在软琼脂分析中，用P50-siRNA处理HC11-Int3细胞可导致菌落形成明显减少。此外，Wap-Int3 / P50基因敲除小鼠没有发生乳腺肿瘤。该数据表明，Notch-4 / Int3激活的NF-κB规范信号依赖于ANK重复序列，不依赖Rbpj，并由IKK激活和P50磷酸化介导，从而引起乳腺肿瘤的发生。用P50-siRNA处理HC11-Int3细胞可导致菌落形成明显减少。此外，Wap-Int3 / P50基因敲除小鼠没有发生乳腺肿瘤。该数据表明，Notch-4 / Int3激活的NF-κB规范信号依赖于ANK重复序列，不依赖Rbpj，并由IKK激活和P50磷酸化介导，从而引起乳腺肿瘤的发生。用P50-siRNA处理HC11-Int3细胞会导致菌落形成明显减少。此外，Wap-Int3 / P50基因敲除小鼠没有发生乳腺肿瘤。该数据表明，Notch-4 / Int3激活的NF-κB规范信号依赖于ANK重复序列，不依赖Rbpj，并由IKK激活和P50磷酸化介导，从而引起乳腺肿瘤的发生。

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The ANK repeats of Notch-4/Int3 activate NF-κB canonical pathway in the absence of Rbpj and causes mammary tumorigenesis.

Transgenic mice expressing the Notch-4 intracellular domain (designated Int3) in the mammary gland have two phenotypes exhibited with 100% penetrance: arrest of mammary alveolar/lobular development and mammary tumorigenesis. Notch-4 signaling is mediated primarily through the interaction of Int3 with the transcription repressor/activator Rbpj. Interestingly, WAP-Int3/Rbpj knockout mice have normal mammary gland development but still developed mammary tumors with a slightly longer latency than the WAP-Int3 mice. Thus, Notch-induced mammary tumor development is Rbpj-independent. Here, we show that Int3 activates NF-κB in HC11 cells in absence of Rbpj through an association with the IKK signalosome. Int3 induced the canonical NF-κB activity and P50 phosphorylation in HC11 cells without altering the NF-κB2 pathway. The minimal domain within the Int3 protein required to activate NF-κB consists of the CDC10/Ankyrin (ANK) repeats domain. Treatment of WAP-Int3 tumor bearing mice with an IKK inhibitor resulted in tumor regression. In a soft agar assay, treatment of HC11-Int3 cells with P50-siRNA caused a significant decrease in colony formation. In addition, Wap-Int3/P50 knockout mice did not develop mammary tumors. This data indicates that the activation of NF-κB canonical signaling by Notch-4/Int3 is ANK repeats dependent, Rbpj-independent, and is mediated by IKK activation and P50 phosphorylation causing mammary tumorigenesis.

更新日期：2017-10-20

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