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.
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.
Lidong
L
Wang
Huibin
H
Yang
Phillip L
PL
Palmbos
Gina
G
Ney
Taylor Ann
TA
Detzler
Dawn
D
Coleman
Jacob
J
Leflein
Mary
M
Davis
Min
M
Zhang
Wenhua
W
Tang
J Kevin
JK
Hicks
Corey M
CM
Helchowski
Jayendra
J
Prasad
Theodore S
TS
Lawrence
Liang
L
Xu
Xiaochun
X
Yu
Christine E
CE
Canman
Mats
M
Ljungman
Diane M
DM
Simeone
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000528:radiation effects; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D000072261:Dishevelled Proteins; D057809:HEK293 Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D010190:Pancreatic Neoplasms / Q000378:metabolism* / Q000532:radiotherapy; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011836:Radiation Tolerance; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays; D000099190:MAP-Kinase-Activated Kinase 2
D048868:Adaptor Proteins, Signal Transducing; D064007:Ataxia Telangiectasia Mutated Proteins; D004268:DNA-Binding Proteins; D000072261:Dishevelled Proteins; D047908:Intracellular Signaling Peptides and Proteins; D010750:Phosphoproteins; D017346:Protein Serine-Threonine Kinases; D014157:Transcription Factors; D000099190:MAP-Kinase-Activated Kinase 2; C087296:TRIM29 protein, human; C576324:ATM protein, human