The infant mouse as a in vivo model for the detection and study of DNA damage-induced changes in the liver.
The present work describes the use of the infant (4-wk-old) mouse as an animal model for the study of DNA damage-induced G(1) checkpoint response, changes in p53 protein levels, and multiple gene expression changes after DNA damage has been induced in the liver. Hepatocytes in the infant B6C3F1 mouse had a proliferation index that was 27 times greater than that of the 12-wk-old B6C3F1 mouse (57.4 vs. 2.1%, respectively). Eight hours after infant mice were exposed to the DNA damaging agents bleomycin (100 mg/kg, i.p.) or 10 Gy of whole body gamma irradiation, the G(1)/S ratio significantly increased from 21 (control) to 66 and 75, respectively, because of the induction of the G(1)/S checkpoint response. One hour after whole body irradiation of infant mice the levels of the p53 protein, phosphoserine 18-p53 and phosphoserine 23-p53 increased dramatically and tended to peak at 1 h in the liver, whereas the p21(WAF1) protein increased more slowly and tended to peak at 2 h after irradiation. The mRNA expression of the p53-response genes p21, murine double minute clone 2 (mdm2), and cyclin G was increased at 2 h after irradiation but was decreased by 8 h postirradiation, relative to the 2-h time-point. The expression of insulin-like growth factor binding protein-1 (IGFBP-1) and growth-regulated oncogene 1 (GRO1) increased at 2 and 8 h postirradiation. This work characterizes various parameters in the infant mouse, thus validating the use of this model to study in vivo DNA damage-induced cell-cycle-related changes.
Reynolds
Randall
R
Department of Comparative Biomedical Sciences, North Carolina State University, Raleigh, North Carolina, USA.
Witherspoon
Sam
S
Fox
Tony
T
D000818:Animals; D000831:Animals, Newborn; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D001761:Bleomycin / Q000633:toxicity; D018797:Cell Cycle Proteins / Q000378:metabolism*; D002455:Cell Division; D054360:Chemokine CXCL1; D019743:Chemokines, CXC / Q000378:metabolism; D056746:Cyclin G; D056766:Cyclin G1; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000378:metabolism; D004247:DNA / Q000187:drug effects / Q000528:radiation effects; D004249:DNA Damage; D004195:Disease Models, Animal; D005720:Gamma Rays / Q000009:adverse effects; D018970:Insulin-Like Growth Factor Binding Protein 1 / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D008099:Liver / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051736:Proto-Oncogene Proteins c-mdm2; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D014916:Whole-Body Irradiation
D000903:Antibiotics, Antineoplastic; C534703:Ccng1 protein, mouse; C493957:Cdkn1a protein, mouse; D018797:Cell Cycle Proteins; D054360:Chemokine CXCL1; D019743:Chemokines, CXC; C475895:Cxcl1 protein, mouse; D056746:Cyclin G; D056766:Cyclin G1; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D018970:Insulin-Like Growth Factor Binding Protein 1; D036341:Intercellular Signaling Peptides and Proteins; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D016159:Tumor Suppressor Protein p53; D001761:Bleomycin; D004247:DNA; C497207:Mdm2 protein, mouse; D051736:Proto-Oncogene Proteins c-mdm2