Atm selectively regulates distinct p53-dependent cell-cycle checkpoint and apoptotic pathways.
Atm is part of a pathway that responds to DNA damage from ionizing radiation (IR). This pathway involves p53, as Atm-deficient cell lines and mice are defective in p53 induction after IR. p53 is a multi-functional protein that simultaneously regulates distinct downstream pathways controlling cell-cycle progression and apoptosis. However, the mechanisms by which p53 differentially activates downstream pathways are unknown. To determine the relationship between Atm and p53, we examined cell-cycle and apoptotic responses in Atm-, p53-(ref. 8) and p21-deficient mice after IR in the whole animal. As expected, p53 protein levels were not induced by IR in thymus of Atm-deficient mice. IR-induced cell-cycle checkpoint function was also defective, and induction of p21 was attenuated in thymus from Atm-deficient mice. However, IR-induced apoptosis and Bax induction were completely normal; both of which are mediated by p53. IR-induced thymic apoptosis was suppressed in Atm/p53 double-mutant mice but not in Atm/p21 double mutants, demonstrating p53 dependence and Atm independence. Thus, Atm deficiency results in lack of p53 induction by IR, but only selective disruption of p53-dependent functions. Our results support a model in which upstream effectors such as Atm selectively activate p53 to regulate specific downstream pathways, providing a mechanism for controlling distinct cell-cycle and apoptotic responses.
Barlow
C
C
Laboratory of Genetic Disease Research, National Institute of Diabetes, Digestive and Kidney Disorders, Bethesda, Maryland 20892, USA.
Brown
K D
KD
Deng
C X
CX
Tagle
D A
DA
Wynshaw-Boris
A
A
D000818:Animals; D017209:Apoptosis / Q000235:genetics* / Q000528:radiation effects; D001260:Ataxia Telangiectasia / Q000235:genetics* / Q000473:pathology; D064007:Ataxia Telangiectasia Mutated Proteins; D002453:Cell Cycle / Q000235:genetics* / Q000528:radiation effects; D018797:Cell Cycle Proteins; D053938:DNA Fragmentation / Q000528:radiation effects; D004253:DNA Nucleotidylexotransferase; D004268:DNA-Binding Proteins; D004195:Disease Models, Animal; D006801:Humans; D017403:In Situ Hybridization; D008168:Lung / Q000378:metabolism / Q000528:radiation effects; D051379:Mice; D018345:Mice, Knockout; D017346:Protein Serine-Threonine Kinases; D011506:Proteins / Q000235:genetics* / Q000502:physiology; D013950:Thymus Gland / Q000378:metabolism / Q000528:radiation effects; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*; D025521:Tumor Suppressor Proteins; D014916:Whole-Body Irradiation
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D011506:Proteins; 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; D004253:DNA Nucleotidylexotransferase