Authors
Li, Yanze Division of Human Genome Science, School of Life Sciences, Faculty of Medicine, Tottori University / Department of Biochemistry and Molecular Biology, Harbin Medical University
Kokura, Kenji Division of Human Genome Science, School of Life Sciences, Faculty of Medicine, Tottori University Tottori University Researchers KAKEN Search Researchers
Inoue, Toshiaki Division of Human Genome Science, School of Life Sciences, Faculty of Medicine, Tottori University Tottori University Researchers KAKEN Search Researchers
Keywords
SIRT2
P/CAF
MDM2
p53
p21
mitotic cell death.
Abstract
We previously reported that the suppression of SIRT2, an NAD + -dependent protein deacetylases, induces p53 accumulation via degradation of p300 and the subsequent MDM2 degradation, eventually leading to apoptosis in HeLa cells. The present study identified a novel pathway of p53 accumulation by SIRT2 suppression in HCT116(p53+/+) cells in which SIRT2 suppression led to escape from mitotic cell death caused by spindle assembly checkpoint activation induced by microtubule inhibitors such as nocodazole but not apoptosis or G1 or G2 arrest. We found that SIRT2 interacts with P/CAF, a histone acetyltransferase, which also acts as a ubiquitin ligase against MDM2. SIRT2 suppression led to an increase of P/CAF acetylation and its stabilization followed by a decrease in MDM2 and activation of the p53-p21 pathway. Depression of mitotic cell death in HCT116(p53+/+) cells with SIRT2 suppression was released by suppression of P/CAF or p21. Thus, the P/CAF-MDM2-p53-p21 axis enables the escape from mitotic cell death and confers resistance to nocodazole in HCT116(p53+/+) cells with SIRT2 suppression. As SIRT2 has attracted attention as a potential target for cancer therapeutics for p53 regulation, the present study provides a molecular basis for the efficacy of SIRT2 for future cancer therapy based on p53 regulation. These findings also suggest an undesirable function of the SIRT2 suppression associated with activation of the p53-p21 pathway in the suppression of mitotic cell death caused by spindle assembly checkpoint activation.
Publisher
Elsevier Inc.
Content Type
Journal Article
Link
ISSN・ISBN
0006291X
NCID
AA11542044
Journal Title
Biochemical and biophysical research communications
Current Journal Title
Biochemical and biophysical research communications
Volume
508
Issue
1
Start Page
230
End Page
236
Published Date
2019-01-01
Publisher-DOI
Text Version
Author
Rights
Copyright © 2018 Elsevier Inc. All rights reserved. This manuscript version is made available under the CC-BY-NC-ND 4.0 license https://creativecommons.org/licenses/by-nc-nd/4.0/
Citation
This work was published by Elsevier : Li, Yanze, Kenji Kokura, and Toshiaki Inoue. "Stabilization of P/CAF, as a ubiquitin ligase toward MDM2, suppresses mitotic cell death through p53-p21 activation in HCT116 cells with SIRT2 suppression." Biochemical and biophysical research communications. 2019, 508(1), 230-236. DOI: https://doi.org/10.1016/j.bbrc.2018.11.136
Department
Faculty of Medicine/Graduate School of Medical Sciences/University Hospital
Language
English