A new transgenic mouse line to image chemically induced p53 activation in vivo.
Monitoring p53 transcriptional activity to identify genotoxic damages induced by drugs has been proposed and validated in vitro. However, this methodology is by design limited to the cell line tested. In this study, we have fully validated a luciferase-based p53-reporter system in vitro and in vivo. We generated a mouse transgenic line to monitor non-invasively p53 activation in response to chemically induced DNA damage. Doxorubicin was used as a drug of known toxicity to validate our model. Reporter gene expression was measured using bioluminescence imaging. In females, a weak p53 luciferase activity driven by a p53-responsive promoter was detectable in the oral cavity region after doxorubicin treatment. In males, the signal increased in the lower abdominal region. Imaging of various organs revealed that the luciferase activity was mainly generated from the testes. Immunohistology demonstrated that the cells in the seminiferous tubules were damaged by the drug and confirmed that they were luciferase and p53 positive. Therefore, these transgenic mice could provide a powerful tool to predict, map and characterize at the organ and cellular levels the toxicity of compounds and help to develop new therapeutic agents in humans.
Briat
Arnaud
A
Centre for Molecular Oncology, Queen Mary's School of Medicine and Dentistry, Charterhouse Square London EC1M 6BQ, UK. Arnaud.Briat@ujf_grenoble.fr
Vassaux
Georges
G
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D004249:DNA Damage; D004317:Doxorubicin / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor / Q000379:methods*; D005260:Female; D015870:Gene Expression / Q000187:drug effects*; D017930:Genes, Reporter; D008156:Luciferases / Q000235:genetics; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D023421:Models, Animal; D011401:Promoter Regions, Genetic / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000032:analysis / Q000235:genetics* / Q000378:metabolism*
D000970:Antineoplastic Agents; D016159:Tumor Suppressor Protein p53; D004317:Doxorubicin; D008156:Luciferases