Abstract
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.
| Original language | English |
|---|---|
| Pages (from-to) | 144-151 |
| Number of pages | 8 |
| Journal | Toxicology |
| Volume | 280 |
| Issue number | 3 |
| DOIs | |
| Publication status | Published - Feb 27 2011 |
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All Science Journal Classification (ASJC) codes
- Toxicology
Cite this
Influence of CLOCK on cytotoxicity induced by diethylnitrosamine in mouse primary hepatocytes. / Naoya, Matsunaga; Kohno, Yumiko; Kakimoto, Keisuke; Hayashi, Akane; Satoru, Koyanagi; Ohdo, Shigehiro.
In: Toxicology, Vol. 280, No. 3, 27.02.2011, p. 144-151.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Influence of CLOCK on cytotoxicity induced by diethylnitrosamine in mouse primary hepatocytes
AU - Naoya, Matsunaga
AU - Kohno, Yumiko
AU - Kakimoto, Keisuke
AU - Hayashi, Akane
AU - Satoru, Koyanagi
AU - Ohdo, Shigehiro
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.
UR - http://www.scopus.com/inward/record.url?scp=79151469758&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=79151469758&partnerID=8YFLogxK
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 -