STAT1–p53 Dynamics Program Cell Fate through p21 and PUMA

Signalling pathways tightly regulate stress-induced cell fate decisions, with p 53 stabilization via attenuation of the p 53– Mdm 2 feedback being central to effective responses. Signal Transducer and Activator of Transcription 1 (STAT1) both represses Mdm2 transcription and co-activates p53 targets ( p21 and PUMA ), yet these dual roles have not been quantified within a unified framework. We build a mechanistic model that couples a biologically calibrated stress scale ( S ) and STAT1 activity (Σ) to the canonical p 53– Mdm 2 core and to downstream p21 and PUMA modules. Key processes are not described by fixed parameters but by explicit functions of S , allowing the model to self-adjust across stress levels without manual re-fitting. This formulation ensures that oscillatory, damped, or plateau responses naturally emerge by varying S alone. STAT1 acts as a dynamical gain on the core (controlling mean level, pulse amplitude, and duration) and as a transcriptional co-activator scaling promoter strengths. Bifurcation analysis reveals a two-dimensional Hopf region in the ( S , Σ) plane; increasing Σ shifts this region to higher S and progressively narrows it, ultimately quenching oscillations at large Σ . Simulations of a generic cell with time-varying S and Σ, combined with a two-stage decision rule (early transient detection followed by stationary readout), map p 53 dynamics to fate: sustained moderate oscillations align with arrest, damped intermediate responses with senescence, and strongly damped high plateaus with apoptosis. The model reproduces cell fate distributions reported in literature for different cell lines (MCF-7, HCT116, U2OS) without kinetic parameter re-fitting, and highlights cell-type-specific sensitivity to p21 versus PUMA . Our framework identifies STAT1 as a tunable amplifier and oscillation quencher of the stress-responsive p53 network, providing testable dynamics-based predictions for fate control.