Autophagy negatively regulates tumor cell proliferation through phosphorylation dependent degradation of the Notch1 intracellular domain

作者：Ahn Ji Seon; Ann Eun Jung; Kim Mi Yeon; Yoon Ji Hye; Lee Hye Jin; Jo Eun Hye; Lee Keesook; Lee Ji Shin; Park Hee Sae^*

来源：Oncotarget, 2016, 7(48): 79033-79049.

DOI：10.18632/oncotarget.12986

• autophagy
• Notch1-IC
• phosphorylation
• degradation
• tumorigenesis

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.

• 出版日期2016-11-29
• 单位河北医科大学