Manic fringe inhibits tumor growth by suppressing Notch3 degradation in lung cancer.
Manic fringe inhibits tumor growth by suppressing Notch3 degradation in lung cancer.
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DOI：
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发表时间：
2013-11
影响因子：
5.3
通讯作者：
Fuming Yi;B. Amarasinghe;T. Dang
中科院分区：
文献类型：
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作者：
Fuming Yi;B. Amarasinghe;T. Dang
Notch信号在发育和癌症中起着重要作用。我们之前已经证明Notch 3对肺癌的生长和生存很重要。Notch受体通过与其配体的相互作用被激活，导致受体的蛋白水解裂解。这种相互作用由Fringe调节，Fringe是岩藻糖特异性β 1，3 N-乙酰葡糖胺转移酶家族，其修饰Notch受体的细胞外亚基。在发育模型中的研究表明，Fringe增强了Notch对Delta配体的反应，而牺牲了Jagged配体。我们观察到Manic Fringe在肺癌中表达下调。由于已知的Notch 3配体Jagged 1通常在肺癌中过度表达，我们假设Fringe负调控Notch 3激活。在这项研究中，我们发现Manic Fringe的重新表达下调了Notch 3靶基因HES 1和HeyL，并在体外和体内减少了肿瘤表型。这种现象的机制似乎与Notch 3蛋白稳定性的调节有关。蛋白酶体抑制逆转躁狂条纹诱导的蛋白质周转。综上所述，我们的数据提供了第一个证据表明，躁狂边缘功能作为一种肿瘤抑制剂在肺，其抗肿瘤活性的机制是通过抑制Notch 3激活介导的。
Notch signaling plays an essential role in development as well as cancer. We have previously shown that Notch3 is important for lung cancer growth and survival. Notch receptors are activated through the interaction with their ligands, resulting in proteolytic cleavage of the receptors. This interaction is modulated by Fringe, a family of fucose-specific β1,3 N-acetylglucosaminyltransferases that modify the extracellular subunit of Notch receptors. Studies in developmental models showed that Fringe enhances Notch's response to Delta ligands at the expense of Jagged ligands. We observed that Manic Fringe expression is down-regulated in lung cancer. Since Jagged1, a known ligand for Notch3, is often over-expressed in lung cancer, we hypothesized that Fringe negatively regulates Notch3 activation. In this study, we show that re-expression of Manic Fringe down-regulates Notch3 target genes HES1 and HeyL and reduces tumor phenotype in vitro and in vivo. The mechanism for this phenomenon appears to be related to modulation of Notch3 protein stability. Proteasome inhibition reverses Manic Fringe-induced protein turnover. Taken together, our data provide the first evidence that Manic Fringe functions as a tumor suppressor in the lung and that the mechanism of its anti-tumor activity is mediated by inhibition of Notch3 activation.