ATDC/TRIM29 Phosphorylation by ATM/MAPKAP Kinase 2 Mediates Radioresistance in Pancreatic Cancer Cells

Lidong Wang(University of Michigan), Huibin Yang(University of Michigan), Phillip L. Palmbos(University of Michigan), Gina M. Ney(University of Michigan), Taylor Detzler(University of Michigan), Dawn M. Coleman(University of Michigan), Jacob Leflein(University of Michigan), Mary A. Davis(University of Michigan), Min Zhang(University of Michigan), Wenhua Tang(University of Michigan), J. Kevin Hicks(University of Michigan), Corey M. Helchowski(University of Michigan), Jayendra Prasad(University of Michigan), Theodore S. Lawrence(University of Michigan), Liang Xu(University of Michigan), Xiaochun Yu(University of Michigan), Christine E. Canman(University of Michigan), Mats Ljungman(University of Michigan), Diane M. Simeone(University of Michigan)
Cancer Research
January 28, 2014
10.1158/0008-5472.can-13-2289
Cited by 64Open Access
Full Text

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.

Related Papers

DNA damage activates ATM through intermolecular autophosphorylation and dimer dissociation
Christopher J. Bakkenist, Michael B. Kastan|Nature|2003|3.4k
ATM and ATR Substrate Analysis Reveals Extensive Protein Networks Responsive to DNA Damage
Shuhei Matsuoka, Bryan A. Ballif, Agata Smogorzewska et al.|Science|2007|3.1k
MDC1 Directly Binds Phosphorylated Histone H2AX to Regulate Cellular Responses to DNA Double-Strand Breaks
Manuel Stucki, Julie A. Clapperton, Duaa H. Mohammad et al.|Cell|2005|1.1k
Substrate Specificities and Identification of Putative Substrates of ATM Kinase Family Members
Seong‐Tae Kim, Dae‐Sik Lim, Christine E. Canman et al.|Journal of Biological Chemistry|1999|810
ATM phosphorylates p95/nbs1 in an S-phase checkpoint pathway
Dae‐Sik Lim, Seong‐Tae Kim, Bo Xu et al.|Nature|2000|777