Atm selectively regulates distinct p53-dependent cell-cycle checkpoint and apoptotic pathways

Nat Genet. 1997 Dec;17(4):453-6. doi: 10.1038/ng1297-453.

Abstract

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.

MeSH terms

  • Animals
  • Apoptosis / genetics*
  • Apoptosis / radiation effects
  • Ataxia Telangiectasia / genetics*
  • Ataxia Telangiectasia / pathology
  • Ataxia Telangiectasia Mutated Proteins
  • Cell Cycle / genetics*
  • Cell Cycle / radiation effects
  • Cell Cycle Proteins
  • DNA Fragmentation / radiation effects
  • DNA Nucleotidylexotransferase
  • DNA-Binding Proteins
  • Disease Models, Animal
  • Humans
  • In Situ Hybridization
  • Lung / metabolism
  • Lung / radiation effects
  • Mice
  • Mice, Knockout
  • Protein-Serine-Threonine Kinases*
  • Proteins / genetics*
  • Proteins / physiology
  • Thymus Gland / metabolism
  • Thymus Gland / radiation effects
  • Tumor Suppressor Protein p53 / genetics*
  • Tumor Suppressor Proteins
  • Whole-Body Irradiation

Substances

  • Cell Cycle Proteins
  • DNA-Binding Proteins
  • Proteins
  • Tumor Suppressor Protein p53
  • Tumor Suppressor Proteins
  • ATM protein, human
  • Ataxia Telangiectasia Mutated Proteins
  • Atm protein, mouse
  • Protein-Serine-Threonine Kinases
  • DNA Nucleotidylexotransferase