title: atm and p53 cooperate in apoptosis and suppression of tumorigenesis, but not in resistance to acute radiation toxicity.
abstract: Mutations in atm and p53 cause the human cancer-associated diseases ataxia-telangiectasia and Li-Fraumeni syndrome, respectively. The two genes are believed to interact in a number of pathways, including regulation of DNA damage-induced cell-cycle checkpoints, apoptosis and radiation sensitivity, and cellular proliferation. Atm-null mice, as well as those null for p53, develop mainly T-cell lymphomas, supporting the view that these genes have similar roles in thymocyte development. To study the interactions of these two genes on an organismal level, we bred mice heterozygous for null alleles of both atm and p53 to produce all genotypic combinations. Mice doubly null for atm and p53 exhibited a dramatic acceleration of tumour formation relative to singly null mice, indicating that both genes collaborate in a significant manner to prevent tumorigenesis. With respect to their roles in apoptosis, loss of atm rendered thymocytes only partly resistant to irradiation-induced apoptosis, whereas additional loss of p53 engendered complete resistance. This implies that the irradiation-induced atm and p53 apoptotic pathways are not completely congruent. Finally-and in contrast to prior predictions-atm and p53 do not appear to interact in acute radiation toxicity, suggesting a separate atm effector pathway for this DNA damage response and having implications for the prognosis and treatment of human tumours.
authors.affiliation: Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: C H
authors.initials: CH
authors.lastname: Westphal
authors.forename: S
authors.initials: S
authors.lastname: Rowan
authors.forename: C
authors.initials: C
authors.lastname: Schmaltz
authors.forename: A
authors.initials: A
authors.lastname: Elson
authors.forename: D E
authors.initials: DE
authors.lastname: Fisher
authors.forename: P
authors.initials: P
authors.lastname: Leder
mesh_terms: D000208:Acute Disease; D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins; D002478:Cells, Cultured; D004268:DNA-Binding Proteins; D003907:Dexamethasone / Q000494:pharmacology; D005260:Female; D017353:Gene Deletion; D005786:Gene Expression Regulation; D006801:Humans; D008297:Male; D051379:Mice; D009374:Neoplasms, Experimental / Q000235:genetics*; D017346:Protein Serine-Threonine Kinases; D011506:Proteins / Q000235:genetics*; D011832:Radiation Injuries; D011836:Radiation Tolerance / Q000235:genetics*; D013950:Thymus Gland / Q000166:cytology / Q000187:drug effects / Q000528:radiation effects; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*; D025521:Tumor Suppressor Proteins
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D011506:Proteins; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D003907:Dexamethasone; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D017346:Protein Serine-Threonine Kinases