Involvement of p53 and p21 in Cellular Defects and Tumorigenesis in Atm(−/−) Mice

Disruption of the mouse Atm gene, whose human counterpart is consistently mutated in ataxia-telangiectasia (A-T) patients, creates an A-T mouse model exhibiting most of the A-T-related systematic and cellular defects. While ATM plays a major role in signaling the p53 response to DNA strand break damage, Atm(−/−) p53(−/−) mice develop lymphomas earlier than Atm(−/−) or p53(−/−) mice, indicating that mutations in these two genes lead to synergy in tumorigenesis. The cell cycle G(1)/S checkpoint is abolished in Atm(−/−) p53(−/−) mouse embryonic fibroblasts (MEFs) following γ-irradiation, suggesting that the partial G(1) cell cycle arrest in Atm(−/−) cells following γ-irradiation is due to the residual p53 response in these cells. In addition, the Atm(−/−) p21(−/−) MEFs are more severely defective in their cell cycle G(1) arrest following γ-irradiation than Atm(−/−) and p21(−/−) MEFs. The Atm(−/−) MEFs exhibit multiple cellular proliferative defects in culture, and an increased constitutive level of p21 in these cells might account for these cellular proliferation defects. Consistent with this notion, Atm(−/−) p21(−/−) MEFs proliferate similarly to wild-type MEFs and exhibit no premature senescence. These cellular proliferative defects are also rescued in Atm(−/−) p53(−/−) MEFs and little p21 can be detected in these cells, indicating that the abnormal p21 protein level in Atm(−/−) cells is also p53 dependent and leads to the cellular proliferative defects in these cells. However, the p21 mRNA level in Atm(−/−) MEFs is lower than that in Atm(+/+) MEFs, suggesting that the higher level of constitutive p21 protein in Atm(−/−) MEFs is likely due to increased stability of the p21 protein.