西亚试剂：Two-phase dynamics of p53 in the DNA damage response

The tumor suppressor p53 mainly induces cell cycle arrest/DNA repair or apoptosis in the DNA damage response. How to choosebetween these two outcomes is not fully understood. We proposed a four-module model of the p53 signaling network and associatedthe network dynamics with cellular outcomes after ionizing radiation. We found that the cellular response is mediated by boththe level and posttranslational modifications of p53 and that p53 is activated in a progressive manner. First, p53 is partiallyactivated by primary modifications such as phosphorylation at Ser-15/20 to induce cell cycle arrest, with its level varyingin a series of pulses. If the damage cannot be fixed after a critical number of p53 pulses, then p53 is fully activated byfurther modifications such as phosphorylation at Ser-46 to trigger apoptosis, with its concentration switching to rather highlevels. Thus, p53 undergoes a two-phase response in irreparably damaged cells. Such combinations of pulsatile and switch-likebehaviors of p53 may represent a flexible and efficient control mode, avoiding the premature apoptosis and promoting the executionof apoptosis. In our model, p53 pulses are recurrently driven by ataxia telangiectasia mutated (ATM) pulses triggered by DNAdamage. The p53-Mdm2 and ATM-p53-Wip1 negative feedback loops are responsible for p53 pulses, whereas the switching behavioroccurs when the p53-PTEN-Akt-Mdm2 positive feedback loop becomes dominant. Our results suggest that a sequential predominanceof distinct feedback loops may elicit multiple-phase dynamical behaviors. This work provides a new mechanism for p53 dynamicsand cell fate decision.