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

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

doi:10.18632/oncotarget.12986

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Research Papers:

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

Ji-Seon Ahn, Eun-Jung Ann, Mi-Yeon Kim, Ji-Hye Yoon, Hye-Jin Lee, Eun-Hye Jo, Keesook Lee, Ji Shin Lee and Hee-Sae Park _

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Oncotarget. 2016; 7:79047-79063. https://doi.org/10.18632/oncotarget.12986

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Abstract

Ji-Seon Ahn1, Eun-Jung Ann1, Mi-Yeon Kim1, Ji-Hye Yoon1, Hye-Jin Lee1, Eun-Hye Jo1, Keesook Lee1, Ji Shin Lee2, Hee-Sae Park1

1Hormone Research Center, School of Biological Sciences and Technology, Chonnam National University, Gwangju 61186, Republic of Korea

2Department of Pathology, Chonnam National University Medical School and Research Institute of Medical Sciences, Gwangju 61469, Republic of Korea

Correspondence to:

Hee-Sae Park, email: [email protected]

Keywords: autophagy, Notch1-IC, phosphorylation, degradation, tumorigenesis

Received: March 29, 2016 Accepted: October 19, 2016 Published: October 27, 2016

ABSTRACT

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.

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Research Papers:

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

Abstract