TY - JOUR
T1 - Involvement of p53 and p21 in cellular defects and tumorigenesis in Atm(-/-) mice
AU - Xu, Yang
AU - Yang, Eva Marie
AU - Brugarolas, James
AU - Jacks, Tyler
AU - Baltimore, David
PY - 1998/7
Y1 - 1998/7
N2 - 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, Atto(-/-) p53(-/-) mice develop lymphomas earlier than Atm(-/-) or p53(-/-) mice, indicating that mutations in these two genes lead to synergy in tumorigehesis. The cell cycle G1/S checkpoint is abolished in Atm(-/-) p53(-/-) mouse embryonic fibroblasts (MEFs) following γ- irradiation, suggesting that the partial G1 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 G1 arrest following γ-irradiation than Atm(-/-) and p21(- /-) MEFs. The Arm(-/-) 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.
AB - 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, Atto(-/-) p53(-/-) mice develop lymphomas earlier than Atm(-/-) or p53(-/-) mice, indicating that mutations in these two genes lead to synergy in tumorigehesis. The cell cycle G1/S checkpoint is abolished in Atm(-/-) p53(-/-) mouse embryonic fibroblasts (MEFs) following γ- irradiation, suggesting that the partial G1 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 G1 arrest following γ-irradiation than Atm(-/-) and p21(- /-) MEFs. The Arm(-/-) 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.
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U2 - 10.1128/MCB.18.7.4385
DO - 10.1128/MCB.18.7.4385
M3 - Article
C2 - 9632822
AN - SCOPUS:0031806910
SN - 0270-7306
VL - 18
SP - 4385
EP - 4390
JO - Molecular and Cellular Biology
JF - Molecular and Cellular Biology
IS - 7
ER -