Two-phase dynamics of p53 in the DNA damage response

Abstract

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

Fig. 1.

Schematic depiction of the integrative model. The model is composed of four modules, separately characterizing the DNA repair, ATM sensor, p53-centered feedback control, and cell fate decision. Four feedback loops are considered, i.e., the p53-Mdm2 and the p53-Wip1-ATM negative feedback loop, and the p53-PTEN-Akt-Mdm2 and the CytoC-Casp3 positive feedback loop. The transactivation of target genes by p53 is denoted by dotted lines. State transition is represented by arrow-headed solid lines, and the promotion and inhibition of state transition are separately denoted by circle-headed and bar-headed lines. Other processes are depicted by arrow-headed double lines.

Fig. 2.

Overview of the dynamics of the p53 network. Time courses of n_c and the levels of ATM^∗, p53^∗, p21, and Casp3 at D_IR = 3 Gy (A) or 5 Gy (B).

Fig. 3.

Initiation of p53 pulses by ATM pulses. (A–B) The bifurcation diagram of ATM^∗ level vs. n_c (A) and that of ATM^∗ level vs. k_swip1 (B) with n_c = 20. The stable and unstable steady states are indicated by thick and thin black lines, respectively. The minima and maxima of the limit cycles are denoted by open circles. (C) A single pulse in the levels of p53^∗, ATM^∗, and Wip1 at D_IR = 1 Gy. (D) Time course of p53^∗ level with k_swip1 = 0 or 0.2 at D_IR = 4 Gy. (E) The bifurcation diagram of p53^∗ level vs. k_smdm2 with n_c = 20. The same convention is used as in panels A and B. (F) The parameter plane spanned by k_swip1 and k_smdm2 is divided into two regions, separately corresponding to oscillatory and nonoscillatory behaviors of p53.

Fig. 4.

Temporal evolution of the levels of proteins in the p53-centered feedback loops at D_IR = 3 Gy (A) or 5 Gy (B).

Fig. 5.

Dynamics of two forms of active p53 and their downstream targets. (A) Time courses of the levels of p53 arrester (black) and p53 killer (red) at D_IR = 5 Gy. (B) Temporal evolution of the levels of p21 (black), Wip1 (red), p53DINP1(green), PTEN (cyan), p53AIP1 (purple), and Casp3 (blue) at D_IR = 5 Gy. (C–D) Time courses of the concentrations of p53 arrester (black), p53 killer (red), and Casp3 (blue) with k_swip1 = 0 and D_IR = 1 Gy (C) or k_swip1 = 0.092 and D_IR = 10 Gy (D). (E) The number of pulses in p53 arrester preceding apoptosis induction, n_ar, as a function of k_swip1. (F) The fraction of apoptotic cells in a population of 2,000 cells, F_A, vs. D_IR with k_swip1 = 0 (red), 0.09 (black), or 0.092 (blue).

Fig. 6.

Effect of PTEN on p53 dynamics and cell fate decision. (A) The bifurcation diagram of p53^∗ level vs. k_sPTEN with n_c = 20. The stable and unstable steady states are indicated by thick and thin black lines, respectively. The minima and maxima of the limit cycles are denoted by open circles. (B) Time courses of the levels of p53 killer and Casp3 with k_sPTEN = 0 (blue), 0.105 (red), or 0.2 (black). (C) The fraction of apoptotic cells in a population of 2,000 cells vs. k_sPTEN at D_IR = 5 Gy. The inset is a zoom in of the curve. (D) The histograms of timing of apoptosis induction, T_A (defined as the time point of Casp3 activation), with k_sPTEN = 0.015 or 0.2. The time bin is 20 min.