We construct a plausible model of p53 regulation in which cell fate decisions in response to irradiation are controlled by interlinked negative and positive feedback loops. Two primary negative feedbacks involve p53 arrester, its p53-responsive inhibitor, Mdm2, and p53-responsive ATM inhibitor, phosphatase Wip1.  Existence of these two feedback loops  enables oscillatory responses to DNA damage which can be terminated when DNA repair is completed (cell recovery) or due to switching to the state of high level of p53 killer (apoptosis). This bistable switch between (1) limit cycle oscillations characterized by high level of p53 arrester and very low level of p53 killer and (2) stable steady state characterized by very high level of p53 killer, arises due to two opposing positive feedback loops stabilizing respectively p53 arrester and p53 killer. The loop which stabilizes p53 arrester involves Wip1: its transcription is regulated by p53 arrester and Wip1 dephosphorylates p53 killer to p53 arrester. The loop which stabilizes p53 killer involves another phosphatase, PTEN, transcription of which is regulated by p53 killer and accumulation of which via  Akt-dependent signaling leads to sequestration of inhibitory Mdm2 in the cytoplasm, and in turn to stabilization of p53 killer at a high level. We analyzed the bifurcation structure of the model and found that, although quite complex, it is possibly the simplest one allowing for the coexistence of stable-period oscillations  and a stable steady state “outside” of the limit cycle. We think that these are the necessary requirements for the plausible model p53 signaling pathway.

In the oscillatory phase, p53 arrester triggers synthesis of p21, leading to the reversible cell cycle arrest, while in the high p53 killer steady state the activation of Bax transcription and inhibition of Akt lead to irreversible apoptosis. Therefore the apoptotic decision is reached via two switches; one allowing for accumulation of p53 killer and PTEN, and inhibition of Akt, the second present in the apoptotic module involving auto-activating caspases.  Analysis of the model demonstrated that cell fate decisions are controlled by expression levels of phosphatases Wip1 and PTEN, and the level of growth factors. These levels are highly variable between cancer cell lines – this can explain differences of their responses to irradiation.