title: 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.
authors.affiliation: Department of Biology, University of California, San Diego, La Jolla, California 92093-0322, USA. yangxu@ucsd.edu
authors.forename: Y
authors.initials: Y
authors.lastname: Xu
authors.forename: E M
authors.initials: EM
authors.lastname: Yang
authors.forename: J
authors.initials: J
authors.lastname: Brugarolas
authors.forename: T
authors.initials: T
authors.lastname: Jacks
authors.forename: D
authors.initials: D
authors.lastname: Baltimore
mesh_terms: D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins; D015197:Carcinogenicity Tests; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000235:genetics / Q000502:physiology*; D004268:DNA-Binding Proteins; D016193:G1 Phase; D005720:Gamma Rays; D006801:Humans; D008223:Lymphoma / Q000209:etiology; D051379:Mice; D010641:Phenotype; D017346:Protein Serine-Threonine Kinases; D011506:Proteins / Q000235:genetics / Q000502:physiology*; D012333:RNA, Messenger; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000502:physiology*; D025521:Tumor Suppressor Proteins
chemical_list: C493956:CDKN1A protein, human; C493957:Cdkn1a protein, mouse; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004268:DNA-Binding Proteins; D011506:Proteins; D012333:RNA, Messenger; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D017346:Protein Serine-Threonine Kinases