TY - JOUR
T1 - Influence of CLOCK on cytotoxicity induced by diethylnitrosamine in mouse primary hepatocytes
AU - Matsunaga, Naoya
AU - Kohno, Yumiko
AU - Kakimoto, Keisuke
AU - Hayashi, Akane
AU - Koyanagi, Satoru
AU - Ohdo, Shigehiro
N1 - Funding Information:
This study was partially supported by a Grant-in-Aid for Scientific Research on Priority Areas “Cancer” (S.O., 20014016 ) from the Ministry of Education, Culture, Sport, Science and Technology of Japan ; a Grant-in-Aid for Scientific Research (B) (S.O., 21390047); a Grant-in-Aid for Challenging Exploratory Research (S.O., 21659041), and a Grant-in-Aid for the Encouragement of Young Scientists (N.M., 20790137) from the Japan Society for the Promotion of Science.
PY - 2011/2/27
Y1 - 2011/2/27
N2 - The Clock gene is a core clock factor that plays an essential role in generating circadian rhythms. In the present study, it was investigated whether the Clock gene affects the response to diethylnitrosamine (DEN)-induced cytotoxicity using mouse primary hepatocytes. DEN-induced cytotoxicity, after 24. h exposure, was caused by apoptosis in hepatocytes isolated from wild-type mouse. On the other hand, Clock mutant mouse (Clk/. Clk) hepatocytes showed resistance to apoptosis. Because apoptosis is an important pathway for suppressing carcinogenesis after genomic DNA damage, the mechanisms that underlie resistance to DEN-induced apoptosis were examined in Clk/. Clk mouse hepatocytes. The mRNA levels of metabolic enzymes bioactivating DEN and apoptosis-inducing factors before DEN exposure were lower in Clk/. Clk cells than in wild-type cells. The accumulation of p53 and Ser15 phosphorylated p53 after 8. h DEN exposure was seen in wild-type cells but not in Clk/. Clk cells. Caspase-3/7 activity was elevated during 24. h DEN exposure in wild-type cells but not in Clk/. Clk cells. In addition, resistance to DEN-induced apoptosis in Clk/. Clk cells affected the cell viability. These studies suggested that the lower expression levels of metabolic enzymes bioactivating DEN and apoptosis inducing factors affected the resistance to DEN-induced apoptosis in Clk/. Clk cells, and the Clock gene plays an important role in cytotoxicity induced by DEN.
AB - The Clock gene is a core clock factor that plays an essential role in generating circadian rhythms. In the present study, it was investigated whether the Clock gene affects the response to diethylnitrosamine (DEN)-induced cytotoxicity using mouse primary hepatocytes. DEN-induced cytotoxicity, after 24. h exposure, was caused by apoptosis in hepatocytes isolated from wild-type mouse. On the other hand, Clock mutant mouse (Clk/. Clk) hepatocytes showed resistance to apoptosis. Because apoptosis is an important pathway for suppressing carcinogenesis after genomic DNA damage, the mechanisms that underlie resistance to DEN-induced apoptosis were examined in Clk/. Clk mouse hepatocytes. The mRNA levels of metabolic enzymes bioactivating DEN and apoptosis-inducing factors before DEN exposure were lower in Clk/. Clk cells than in wild-type cells. The accumulation of p53 and Ser15 phosphorylated p53 after 8. h DEN exposure was seen in wild-type cells but not in Clk/. Clk cells. Caspase-3/7 activity was elevated during 24. h DEN exposure in wild-type cells but not in Clk/. Clk cells. In addition, resistance to DEN-induced apoptosis in Clk/. Clk cells affected the cell viability. These studies suggested that the lower expression levels of metabolic enzymes bioactivating DEN and apoptosis inducing factors affected the resistance to DEN-induced apoptosis in Clk/. Clk cells, and the Clock gene plays an important role in cytotoxicity induced by DEN.
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U2 - 10.1016/j.tox.2010.12.005
DO - 10.1016/j.tox.2010.12.005
M3 - Article
C2 - 21167249
AN - SCOPUS:79151469758
VL - 280
SP - 144
EP - 151
JO - Toxicology
JF - Toxicology
SN - 0300-483X
IS - 3
ER -