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首页> 外文期刊>Molecular and Cellular Biology >Notch Signaling Induces Rapid Degradation of Achaete-Scute Homolog 1
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Notch Signaling Induces Rapid Degradation of Achaete-Scute Homolog 1

机译：Notch信号诱导Achaete-Scute同源物1的快速降解

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In neural development, Notch signaling plays a key role in restricting neuronal differentiation, promoting the maintenance of progenitor cells. Classically, Notch signaling causes transactivation of Hairy-enhancer of Split (HES) genes which leads to transcriptional repression of neural determination and differentiation genes. We now report that in addition to its known transcriptional mechanism, Notch signaling also leads to rapid degradation of the basic helix-loop-helix (bHLH) transcription factor human achaete-scute homolog 1 (hASH1). Using recombinant adenoviruses expressing active Notch1 in small-cell lung cancer cells, we showed that the initial appearance of Notch1 coincided with the loss of hASH1 protein, preceding the full decay of hASH1 mRNA. Overexpression of HES1 alone was capable of down-regulating hASH1 mRNA but could not replicate the acute reduction of hASH1 protein induced by Notch1. When adenoviral hASH1 was coinfected with Notch1, we still observed a dramatic and abrupt loss of the exogenous hASH1 protein, despite high levels of ongoing hASH1 RNA expression. Notch1 treatment decreased the apparent half-life of the adenoviral hASH1 protein and increased the fraction of hASH1 which was polyubiquitinylated. The proteasome inhibitor MG132 reversed the Notch1-induced degradation. The Notch RAM domain was dispensable but a lack of the OPA and PEST domains inactivated this Notch1 action. Overexpression of the hASH1-dimerizing partner E12 could protect hASH1 from degradation. This novel function of activated Notch to rapidly degrade a class II bHLH protein may prove to be important in many contexts in development and in cancer.
机译：在神经发育中，Notch信号在限制神经元分化，促进祖细胞维持中起关键作用。经典地，Notch信号传导导致分裂毛状增强子（HES）基因的反式激活，从而导致神经测定和分化基因的转录抑制。我们现在报告，除了其已知的转录机制，Notch信号还导致基本螺旋-环-螺旋（bHLH）转录因子人类achaete-scute同源物1（hASH1）的快速降解。使用在小细胞肺癌细胞中表达活性Notch1的重组腺病毒，我们显示Notch1的最初出现与hASH1蛋白的丢失相吻合，然后才完全降解hASH1 mRNA。仅HES1的过表达能够下调hASH1 mRNA，但不能复制Notch1诱导的hASH1蛋白的急性减少。当腺病毒hASH1与Notch1共感染时，尽管正在进行的hASH1 RNA表达水平很高，但我们仍然观察到外源性hASH1蛋白的急剧突变。 Notch1处理降低了腺病毒hASH1蛋白的表观半衰期，并增加了被泛素化的hASH1的比例。蛋白酶体抑制剂MG132逆转了Notch1诱导的降解。 Notch RAM域是可有可无的，但是缺少OPA和PEST域使该Notch1操作无效。 hASH1二聚体伴侣E12的过表达可以保护hASH1免受降解。活化的Notch能够快速降解II类bHLH蛋白的这种新功能在开发和癌症中的许多情况下可能被证明是重要的。

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