Autophagy negatively regulates tumor cell proliferation through phosphorylation dependent degradation of the Notch1 intracellular domain.
Autophagy negatively regulates tumor cell proliferation through phosphorylation dependent degradation of the Notch1 intracellular domain.
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DOI：
10.18632/oncotarget.12986
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发表时间：
2016-11-29
期刊：
影响因子：
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通讯作者：
Park HS
中科院分区：
文献类型：
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作者：
Ahn JS;Ann EJ;Kim MY;Yoon JH;Lee HJ;Jo EH;Lee K;Lee JS;Park HS
自噬是一种高度保守的机制，可以降解长寿蛋白和功能失调的细胞器，并决定细胞的命运。在本研究中，自噬通过降解Notch1胞内域(Notch1-IC)来减弱Notch1信号。营养缺乏促进了MEKK1对Notch1-IC的磷酸化，而磷酸化的Notch1-IC被Fbw7 E3连接酶识别。Fbw7泛素化Notch1-IC对于Notch1-IC与p62的相互作用和聚集体的形成是必不可少的。抑制Notch1信号可阻止乳腺癌细胞转化、肿瘤进展和转移。乳腺癌组织中Notch1和p62的表达与Beclin1的表达呈负相关。这些结果表明，自噬通过促进Notch1-IC的降解来抑制Notch1信号，从而在肿瘤抑制中发挥作用。
Autophagy is a highly conserved mechanism that degrades long-lived proteins and dysfunctional organelles, and contributes to cell fate. In this study, autophagy attenuates Notch1 signaling by degrading the Notch1 intracellular domain (Notch1-IC). Nutrient-deprivation promotes Notch1-IC phosphorylation by MEKK1 and phosphorylated Notch1-IC is recognized by Fbw7 E3 ligase. The ubiquitination of Notch1-IC by Fbw7 is essential for the interaction between Notch1-IC and p62 and for the formation of aggregates. Inhibition of Notch1 signaling prevents the transformation of breast cancer cells, tumor progression, and metastasis. The expression of Notch1 and p62 is inversely correlated with Beclin1 expression in human breast cancer patients. These results show that autophagy inhibits Notch1 signaling by promoting Notch1-IC degradation and therefore plays a role in tumor suppression.