Radiation-induced micronuclei in p53-deficient and normal mice
- Microbiological Assoc., Rockville, MD (United States)
- GenPharm Int., Mountain View, CA (United States)
- Johns Hopkins Univ. Oncology Center, Baltimore, MD (United States)
Mutations in the p53 tumor suppressor gene are the most frequent genetic alteration observed in human tumors. One proposed function for the p53 protein is to monitor DNA for the presence of damage and prevent a cell from performing scheduled DNA synthesis on a damaged template. We have investigated this hypothesis by subjecting homozygous p53 deficient mice (TSG-p53{reg_sign}) and wild type controls to various doses of ionizing radiation and collecting bone marrow for quantitation of micronuclei at increasing times following exposure. Neither p53 deficient nor wild type animals showed increased frequencies of micronuclei when bone marrow was harvested at 6 hours after irradiation with 1, 2, and 3 Gy. Transgenic and wild type mice sacrificed 24 hours after irradiation showed increased frequencies of micronuclei with no concomitant alteration in the ratios of polychromatic erythrocytes (PCE) to total erythrocytes (TE) (a measure of toxicity). Wild type animals sacrificed 48 hours after irradiation showed no elevation in frequencies of micronuclei and severe reduction in the PCE:TE ratio. p53 deficient animals sacrificed at 48 hours showed dos-related increases in micronuclei up to 17.2 micronucleated PCEs/1000 cells at 3Gy with no change in the PCE:TE ratio. The results suggest: (1) Cells exposed to radiation after G{sub 1} continue to cycle and produce micronuclei regardless of their p53 status. (2) p53 deficient cells irradiated before G{sub 1} show increased chromosomal damage and no inhibition in the production of PCE while similarly treated wild type cells appear almost completely blocked. These observations support the hypothesis that p53 acts to detect DNA damage and arrest cells in G{sub 1} to effect repair.
- OSTI ID:
- 88883
- Report Number(s):
- CONF-9405324--; CNN: Grant NCI SBIR 1 R43 CA55471-0
- Journal Information:
- Environmental and Molecular Mutagenesis, Journal Name: Environmental and Molecular Mutagenesis Journal Issue: Suppl.23 Vol. 23; ISSN 0893-6692; ISSN EMMUEG
- Country of Publication:
- United States
- Language:
- English
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