MEPE/OF45 protects cells from DNA damage induced killing via stabilizing CHK1.

Authors

Shuang Liu, Beijing Institute of Biotechnology, Beijing 100850, China; Department of Radiation Oncology, Winship Cancer Institute, Emory UniversityFollow
Hongyan Wang, Department of Radiation Oncology, Winship Cancer Institute, Emory UniversityFollow
Xiang Wang, Department of Radiation Oncology, Thomas Jefferson UniversityFollow
Lin Lu, Department of Radiation Oncology, Thomas Jefferson UniversityFollow
Ning Gao, Beijing Institute of Biotechnology, Beijing 100850, China
Peter S N Rowe, Department of Internal Medicine, Kidney Institute & Division of Nephrology, University of Kansas Medical Center
Baocheng Hu, Beijing Institute of Biotechnology, Beijing 100850, China; Department of Radiation Oncology, Winship Cancer Institute, Emory UniversityFollow
Ya Wang, Department of Radiation Oncology, Winship Cancer Institute, Emory University

Document Type

Article

Publication Date

12-1-2009

Comments

This article has been peer reviewed. It was published in: Nucleic Acids Research.

Volume 37, Issue 22, December 2009, Pages 7447–54.

The published version is available at http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2794162/?report=classic

DOI: 10.1093/nar/gkp768

Copyright © The Author(s) 2009. Published by Oxford University Press

Abstract

Matrix extracellular phosphoglycoprotein/osteoblast factor 45 (MEPE/OF45) was cloned in 2000 with functions related to bone metabolism. We identified MEPE/OF45 for the first time as a new co-factor of CHK1 in mammalian cells to protect cells from DNA damage induced killing. We demonstrate here that MEPE/OF45 directly interacts with CHK1. Knocking down MEPE/OF45 decreases CHK1 levels and sensitizes the cells to DNA damage inducers such as ionizing radiation (IR) or camptothicin (CPT)-induced killing. Over-expressing wild-type MEPE/OF45, but not the mutant MEPE/OF45 (depleted the key domain to interact with CHK1) increases CHK1 levels in the cells and increases the resistance of the cells to IR or CPT. MEPE/OF45, interacting with CHK1, increases CHK1 half-life and decreases CHK1 degradation through the ubiquitine-mediated pathway. In addition, the interaction of MEPE/OF45 with CHK1 decreases CHK1 levels in the ubiquitin E3 ligases (Cul1 and Cul4A) complex, which suggests that MEPE/OF45 competes with the ubiquitin E3 ligases binding to CHK1 and thus decreases CHK1 from ubiquitin-mediated proteolysis. These findings reveal an important role of MEPE/OF45 in protecting cells from DNA damage induced killing through stabilizing CHK1, which would provide MEPE/OF45 as a new target for sensitizing tumor cells to radiotherapy or chemotherapy.

Recommended Citation

Liu, Shuang; Wang, Hongyan; Wang, Xiang; Lu, Lin; Gao, Ning; Rowe, Peter S N; Hu, Baocheng; and Wang, Ya, "MEPE/OF45 protects cells from DNA damage induced killing via stabilizing CHK1." (2009). Department of Radiation Oncology Faculty Papers. Paper 35.
https://jdc.jefferson.edu/radoncfp/35

PubMed ID

19808933