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

Xu, Yang and Yang, Eva Marie and Brugarolas, James and Jacks, Tyler and Baltimore, David (1998) Involvement of p53 and p21 in Cellular Defects and Tumorigenesis in Atm^(−/−) Mice. Molecular and Cellular Biology, 18 (7). pp. 4385-4390. ISSN 0270-7306. PMCID PMC109022. doi:10.1128/mcb.18.7.4385.

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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.

Item Type:Article
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URLURL TypeDescription CentralArticle
Baltimore, David0000-0001-8723-8190
Additional Information:© 1998, American Society for Microbiology. Received 10 March 1998/Accepted 13 April 1998 This project was partially supported by a National Institute of Health grant to D.B. and grants from AT Childrens Projects to D.B. and Y.X. Y.X. was partly supported by the Cancer Research Fund of the Damon Runyon-Walter Winchell Foundation. D.B. is an American Cancer Society Research Professor.
Funding AgencyGrant Number
Ataxia TelangiectasiaUNSPECIFIED
Damon Runyon-Walter Winchell Cancer FundUNSPECIFIED
American Cancer SocietyUNSPECIFIED
Issue or Number:7
PubMed Central ID:PMC109022
Record Number:CaltechAUTHORS:XUYmcb98
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Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:2815
Deposited By: Archive Administrator
Deposited On:28 Apr 2006
Last Modified:08 Nov 2021 19:51

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