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J. Biol. Chem., Vol. 278, Issue 38, 36676-36687, September 19, 2003

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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 ¶ and Kyung Hwan Kim 

From the Department of Pharmacology and Institute of Gastroenterology, Brain Korea 21 Project for Medical Science, Yonsei University College of Medicine, Seoul 120-752, Korea and the ^¶Department of General Medicine, Tokyo Medical and Dental University School of Medicine, Tokyo 113-8519, Japan

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 -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 and importin reflects possible modification of nuclear import of Ku proteins. The importin 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.

Received for publication, April 9, 2003 , and in revised form, July 14, 2003.

^* This study was supported by a grant from the Korean Ministry of Health and Welfare (to H. K.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed. Tel.: 82-2-361-5232; Fax: 8-2-313-1894; E-mail: kim626{at}yumc.yonsei.ac.kr.

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