Atm selectively regulates distinct p53-dependent cell-cycle checkpoint and apoptotic pathways - PubMed (original) (raw)
Atm selectively regulates distinct p53-dependent cell-cycle checkpoint and apoptotic pathways
C Barlow et al. Nat Genet. 1997 Dec.
Erratum in
- Nat Genet 1998 Mar;18(3):298
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.
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