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

By Shuang Liu, Hongyan Wang, Xiang Wang, Lin Lu, Ning Gao, Peter S N Rowe, Baocheng Hu and Ya Wang

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

Topics: Animals, Cell Line, Transformed, Cytoprotection, DNA Damage, Enzyme Stability, Extracellular Matrix Proteins, Glycoproteins, Phosphoproteins, Protein Kinases, Rats, Ubiquitins, Cell Line, Transformed, Oncology
Publisher: Jefferson Digital Commons
Year: 2009
OAI identifier: oai:jdc.jefferson.edu:radoncfp-1038

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