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Cancer Res. 2014 Mar 15;74(6):1778-88. doi: 10.1158/0008-5472.CAN-13-2289. Epub 2014 Jan 27.

ATDC/TRIM29 phosphorylation by ATM/MAPKAP kinase 2 mediates radioresistance in pancreatic cancer cells.

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1
Authors' Affiliations: Departments of Surgery, Radiation Oncology, Pharmacology, Internal Medicine and Molecular and Integrative Physiology, Translational Oncology Program, and Pediatrics and Communicable Diseases, University of Michigan Medical School, Ann Arbor, Michigan.

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is characterized by therapeutic resistance for which the basis is poorly understood. Here, we report that the DNA and p53-binding protein ATDC/TRIM29, which is highly expressed in PDAC, plays a critical role in DNA damage signaling and radioresistance in pancreatic cancer cells. Ataxia-telangiectasia group D-associated gene (ATDC) mediated resistance to ionizing radiation in vitro and in vivo in mouse xenograft assays. ATDC was phosphorylated directly by MAPKAP kinase 2 (MK2) at Ser550 in an ATM-dependent manner. Phosphorylation at Ser-550 by MK2 was required for the radioprotective function of ATDC. Our results identify a DNA repair pathway leading from MK2 and ATM to ATDC, suggesting its candidacy as a therapeutic target to radiosensitize PDAC and improve the efficacy of DNA-damaging treatment.

PMID:
24469230
PMCID:
PMC3961828
DOI:
10.1158/0008-5472.CAN-13-2289
[Indexed for MEDLINE]
Free PMC Article
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