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

Abstract

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 G1/S checkpoint is abolished in Atm-/- p53-/- mouse embryonic fibroblasts (MEFs) following gamma -irradiation, suggesting that the partial G1 cell cycle arrest in Atm-/- cells following gamma -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 G1 arrest following gamma -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.