Abstract
In wildtype (p53+/+) mice, p53-dependent and -independent DNA repair mechanisms restore damaged DNA. Irreparably damaged cells are then effectively removed by p53-dependent apoptosis after low dose rate radiation (LDR). Therefore, the teratogenic rate is the same as that of non-irradiated controls. In contrast, only the p53-independent DNA repair mechanism works in knockout (p53-/-) mice; p53-dependent DNA repair and apoptosis do not work. So the teratogenic rate does not decrease to a control level in p53+/+ mice even at low dose rate irradiation. DNA damage after LDR is thought to be caused by mechanisms similar to those involved in the processes of carcinogenesis and teratogenesis. This study examined whether p53 can remove damage not only via a DNA repair mechanism but also by apoptosis during a radiation-induced carcinogenic process.
The backs of seven-week-old mice (p53+/+, p53+/-, and p53-/-) were irradiated with beta-rays three times a week until a tumor appeared or throughout the life of the mice. Group I received 2.5 Gy/day, while Group II received 5 Gy/day. Group III received 7.5 Gy/day, but was only for p53-/- mice. The p53 gene from each tumor was analyzed for mutations and loss of heterozygosity (LOH).
No tumors appeared in any of the p53-/- animals. It seems that life of this mouse will be too short to observe radiation carcinogenesis. However, tumors did occur in the p53+/- mice, with an incidence of 8/21 in Group I and 25/46 in Group II. Tumors were also found in the p53+/+ mice; 8/28 in Group I and 6/33 in Group II appeared about 150 days later than those of the p53+/- mice. Of 23 heterozygote tumors examined, 14 exhibited LOH of the p53 gene but no mutations. In p53+/+ mice, 7/9 of tumors had mutations and 3/9 had LOH.
The status of a p53 gene obviously affects the incidence and time of tumor formation. One of the reasons may be that the types of radiation induced abnormality of p53 gene vary with the status of a p53 gene.
