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Oxidative stress induces nuclear loss of DNA repair proteins Ku70 and Ku80 and apoptosis in pancreatic acinar AR42J cells.

 Ji Yeon Song  ;  Joo Weon Lim  ;  Hyeyoung Kim  ;  Tomohiro Morio  ;  Kyung Hwan Kim 
 JOURNAL OF BIOLOGICAL CHEMISTRY, Vol.278(38) : 36676-36687, 2003 
Journal Title
Issue Date
Antigens, Nuclear/biosynthesis* ; Apoptosis ; Blotting, Western ; Caspase 3 ; Caspase Inhibitors ; Cell Death ; Cell Line, Tumor ; Cell Nucleus/metabolism* ; Cell Survival ; Cytoplasm/metabolism ; DNA Fragmentation ; DNA Helicases* ; DNA Repair* ; DNA, Complementary/metabolism ; DNA-Binding Proteins/biosynthesis* ; Dose-Response Relationship, Drug ; Enzyme Inhibitors/pharmacology ; Genes, Dominant ; Glucose Oxidase/metabolism ; Glutathione Transferase/metabolism ; Humans ; Hydrogen Peroxide/pharmacology ; Ku Autoantigen ; Microscopy, Fluorescence ; Oxidative Stress* ; Pancreas/cytology* ; Plasmids/metabolism ; Protein Binding ; Proto-Oncogene Proteins/metabolism ; Proto-Oncogene Proteins c-bcl-2/metabolism ; Recombinant Fusion Proteins/metabolism ; Time Factors ; Transfection ; Tumor Suppressor Protein p53/metabolism ; alpha Karyopherins/chemistry ; bcl-2-Associated X Protein ; beta Karyopherins/metabolism
Cell death linked to oxidative DNA damage has been implicated in acute pancreatitis. The severe DNA damage, which is beyond the capacity of the DNA repair proteins, triggers apoptosis. It has been hypothesized that oxidative stress may induce a decrease in the Ku70 and Ku80 levels and apoptosis in pancreatic acinar cells. In this study, it was found that oxidative stress caused by glucose oxidase (GO) acting on beta-d-glucose, glucose/glucose oxidase (G/GO), induced slight changes in cytoplasmic Ku70 and Ku80 but drastically induced a decrease in nuclear Ku70 and Ku80 both time- and concentration-dependently in AR42J cells. G/GO induced apoptosis determined by poly(ADP-ribose) polymerase cleavage, an increase in expression of p53 and Bax, and a decrease in Bcl-2 expression. G/GO-induced apoptosis was in parallel with the loss of nuclear Ku proteins in AR42J cells. Caspase-3 inhibitor prevented G/GO-induced nuclear Ku loss and cell death. G/GO did not induce apoptosis in the cells transfected with either the Ku70 or Ku80 expression gene but increased apoptosis in those transfected with the Ku dominant negative mutant. Pulse and pulse-chase results show that G/GO induced Ku70 and Ku80 syntheses, even though Ku70 and Ku80 were degraded both in cytoplasm and nucleus. G/GO-induced decrease in Ku binding to importin alpha and importin beta reflects possible modification of nuclear import of Ku proteins. The importin beta level was not changed by G/GO. These results demonstrate that nuclear decrease in Ku70 and Ku80 may result from the decrease in Ku binding to nuclear transporter importins and the degradation of Ku proteins. The nuclear loss of Ku proteins may underlie the mechanism of apoptosis in pancreatic acinar cells after oxidative stress.
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1. College of Medicine (의과대학) > Dept. of Pharmacology (약리학교실) > 1. Journal Papers
Yonsei Authors
Kim, Kyung Hwan(김경환)
Lim, Joo Weon(임주원)
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