ATDC/TRIM29 phosphorylation by ATM/MAPKAP kinase 2 mediates radioresistance in pancreatic cancer cells.
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.
Mesh Terms:
Adaptor Proteins, Signal Transducing, Animals, Ataxia Telangiectasia Mutated Proteins, Cell Line, Tumor, Cell Survival, DNA-Binding Proteins, Dishevelled Proteins, HEK293 Cells, Humans, Intracellular Signaling Peptides and Proteins, Mice, Mice, Inbred NOD, Mice, SCID, Pancreatic Neoplasms, Phosphoproteins, Phosphorylation, Protein Processing, Post-Translational, Protein-Serine-Threonine Kinases, Radiation Tolerance, Transcription Factors, Xenograft Model Antitumor Assays
Adaptor Proteins, Signal Transducing, Animals, Ataxia Telangiectasia Mutated Proteins, Cell Line, Tumor, Cell Survival, DNA-Binding Proteins, Dishevelled Proteins, HEK293 Cells, Humans, Intracellular Signaling Peptides and Proteins, Mice, Mice, Inbred NOD, Mice, SCID, Pancreatic Neoplasms, Phosphoproteins, Phosphorylation, Protein Processing, Post-Translational, Protein-Serine-Threonine Kinases, Radiation Tolerance, Transcription Factors, Xenograft Model Antitumor Assays
Cancer Res.
Date: Mar. 15, 2014
PubMed ID: 24469230
View in: Pubmed Google Scholar
Download Curated Data For This Publication
199681
Switch View:
- Interactions 3