A model of STAT1-p53 coordination: Regulating p21 and PUMA to program cell fate under stress

Signalling pathways tightly regulate stress-induced cell fate decisions, with p53 stabilization via attenuation of the p53-Mdm2 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 p53-Mdm2 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. The model is calibrated to reproduce the pulsatile/oscillatory p53 regime typically observed under DNA-damage stresses that generate DNA double-strand breaks (DSBs), such as ionizing radiation and radiomimetic or topoisomerase-targeting agents. STAT1 controls and acts 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 p53 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.