Heterozygous p53-deficient (+/-) mice develop fewer p53-negative preneoplastic focal liver lesions in response to treatment with diethylnitrosamine than do wild-type (+/+) mice.
In the present study p53+/- and p53+/+C57BL/6 female mice were administered diethylnitrosamine (DEN) once each week for 15-20 weeks. After sacrifice we analyzed the number and size of preneoplastic liver lesions, and found that the same numbers of lesions of similar sizes developed in the two genotypes of mice. We also distinguished between two phenotypes: 'p53-positive' and 'p53-negative' lesions (i.e. lesions with or without a p53 response to DNA damage, as assessed by immunohistochemical staining for p53 24 h after administration of a challenging dose of DEN). In wild-type mice we found the same proportion of p53-positive and p53-negative lesions as in rats, i.e. about 75% of the lesions were p53-negative. However, the number and the percentage of p53-negative lesions were lower in +/- mice (17%, P < 0.05). These results were confirmed by Western blot analysis revealing a clear p53 response in lesions only in the case of +/- mice. These findings support our previous conclusion that an attenuated p53 response in preneoplastic lesions compared to normal tissue may give these lesions a growth advantage under conditions of subchronic genotoxic stress. Furthermore, our findings suggest that the presence of only one functional p53 allele in p53+/- mice is sufficient to counteract the growth advantage that such an attenuated p53 response appears to confer.
Finnberg
Niklas
N
Institute of Environmental Medicine, Karolinska Institutet, Box 210, S-171 77 Stockholm, Sweden.
Stenius
Ulla
U
Högberg
Johan
J
D000818:Animals; D042846:CDC2-CDC28 Kinases / Q000378:metabolism; D002273:Carcinogens / Q000633:toxicity*; D006528:Carcinoma, Hepatocellular / Q000378:metabolism* / Q000473:pathology; D051357:Cyclin-Dependent Kinase 2; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000378:metabolism; D004052:Diethylnitrosamine / Q000633:toxicity*; D005260:Female; D006579:Heterozygote; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008114:Liver Neoplasms, Experimental / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009687:Nuclear Proteins / Q000378:metabolism; D011230:Precancerous Conditions / Q000378:metabolism* / Q000473:pathology; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051736:Proto-Oncogene Proteins c-mdm2; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000502:physiology*
D002273:Carcinogens; C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D016159:Tumor Suppressor Protein p53; D004052:Diethylnitrosamine; C497207:Mdm2 protein, mouse; D051736:Proto-Oncogene Proteins c-mdm2; D042846:CDC2-CDC28 Kinases; C495893:Cdk2 protein, mouse; D051357:Cyclin-Dependent Kinase 2