Coordination between p21 and DDB2 in the cellular response to UV radiation

Abstract

The tumor suppressor p53 guides the cellular response to DNA damage mainly by regulating expression of target genes. The cyclin-dependent kinase inhibitor p21, which is induced by p53, can both arrest the cell cycle and inhibit apoptosis. Interestingly, p53-inducible DDB2 (damaged-DNA binding protein 2) promotes apoptosis by mediating p21 degradation after ultraviolet (UV)-induced DNA damage. Here, we developed an integrated model of the p53 network to explore how the UV-irradiated cell makes a decision between survival and death and how the activities of p21 and DDB2 are modulated. By numerical simulations, we found that p53 is activated progressively and the promoter selectivity of p53 depends on its concentration. For minor DNA damage, p53 settles at an intermediate level. p21 is induced by p53 to arrest the cell cycle via inhibiting E2F1 activity, allowing for DNA repair. The proapoptotic genes are expressed at low levels. For severe DNA damage, p53 undergoes a two-phase behavior and accumulates to high levels in the second phase. Consequently, those proapoptotic proteins accumulate remarkably. Bax activates the release of cytochrome c, while DDB2 promotes the degradation of p21, which leads to activation of E2F1 and induction of Apaf-1. Finally, the caspase cascade is activated to trigger apoptosis. We revealed that the downregulation of p21 is necessary for apoptosis induction and PTEN promotes apoptosis by amplifying p53 activation. This work demonstrates that how the dynamics of the p53 network can be finely regulated through feed-forward and feedback loops within the network and emphasizes the importance of p21 regulation in the DNA damage response.

Figure 1. Schematic diagram of the model for the p53 network responding to UV-induced DNA damage.

The model is composed of four modules. Two p53-centered feedback loops are considered: the p53-Mdm2 negative feedback loop and the p53-PTEN-Akt-Mdm2 positive feedback loop. Cell cycle arrest is induced through p21-dependent inhibition of E2F1, while apoptosis is triggered via the caspase cascade activated by Bax and Apaf-1. Dashed lines denote gene expression induced by p53 and E2F1. Solid arrowed lines represent transitions between proteins, promotion or inhibition of which is denoted by circle-headed and bar-headed lines, respectively.

Figure 2. Dynamics of key components of the p53 network.

Temporal evolution of the levels of DNA damage, ATR_p, p53_p, p21_tot, Bax, and Casp3 (from top to bottom) at (A) or 20 (B).

Figure 3. Switching behavior of ATR as a sensor of DNA damage.

(A) Bifurcation diagram of [ATR_p] vs. (without DNA repair). (B) Time courses of [ATR_p] at (black), 10 (red), or 20 (blue).

Figure 4. Role of PTEN in the two-phase dynamics of [p53_p].

(A) Time courses of [p53_p] at (black), 10 (red), or 20 (blue). (B) Maximum of [p53_p] throughout the cellular response vs. . (C) Bifurcation diagram of [p53_p] vs. the p53-inducible production rate of PTEN, , at fixed . (D) Time courses of [p53_p] with (black) or 0.05 (red).

Figure 5. Regulation of cell cycle progression and apoptosis by p21.

(A) Time courses of [p21_tot] (black), [Rb_p] (red), and [E2F1] (blue) at . (B) Time courses of [p21_tot] (black), [E2F1] (green), [Apaf-1] (red), and [Casp9] (blue) at . (C) Bifurcation diagram of [E2F1] vs. the p53-inducible production rate of p21, . (D) Time courses of [p21_tot] (black), [E2F1] (blue), [CytoC] (red), and [Casp9] (green) with and .

Figure 6. DDB2 promotes apoptosis via mediating the degradation of p21.

(A) Time courses of [DDB2] at 5 (black) or 20 (red). (B) Bifurcation diagram of [p21_tot] vs. the p53-inducible production rate of DDB2, . (C) Time courses of [p21_tot] (black), [E2F1] (green), [Bax] (red), and [Casp9] (blue) with at . (D) Time courses of [Casp9] with the normal parameter setting (i.e., and ) (black), and (blue), or and (red).