泛素连接酶
Notch信号通路
泛素
平方毫米
细胞生物学
锚蛋白重复序列
麻木的
信号
生物
脱氮酶
Hes3信号轴
细胞命运测定
信号转导
Notch蛋白质类
化学
细胞凋亡
生物化学
转录因子
基因
作者
Susanne Pettersson,Matylda Sczaniecka,Lorna McLaren,Fiona Margaret M Russell,Karen Gladstone,Ted R. Hupp,Maura Wallace
摘要
The Notch receptor is necessary for modulating cell fate decisions throughout development, and aberrant activation of Notch signalling has been associated with many diseases, including tumorigenesis. The E3 ligase MDM2 (murine double minute 2) plays a role in regulating the Notch signalling pathway through its interaction with NUMB. In the present study we report that MDM2 can also exert its oncogenic effects on the Notch signalling pathway by directly interacting with the Notch 1 receptor through dual-site binding. This involves both the N-terminal and acidic domains of MDM2 and the RAM [RBP-Jκ (recombination signal-binding protein 1 for Jκ)-associated molecule] and ANK (ankyrin) domains of Notch 1. Although the interaction between Notch1 and MDM2 results in ubiquitination of Notch1, this does not result in degradation of Notch1, but instead leads to activation of the intracellular domain of Notch1. Furthermore, MDM2 can synergize with Notch1 to inhibit apoptosis and promote proliferation. This highlights yet another target for MDM2-mediated ubiquitination that results in activation of the protein rather than degradation and makes MDM2 an attractive target for drug discovery for both the p53 and Notch signalling pathways.
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