Fig. 2.

Model of the p53–Mdm2 oscillator. Two forms of p53 in the nucleus are considered, inactive p53 and active p53*. Mdm2 in the nucleus and cytoplasm is denoted as Mdm2_nuc and Mdm2_cyt, respectively. They can shuttle between the two compartments at rates k_i and k_o. Inactive p53 is degraded rapidly by Mdm2 at a rate k_d53, whereas active p53* is degraded slowly at a rate k_d53* because of its weak binding affinity to Mdm2_nuc. Combined negative (red lines) and positive (blue lines) feedback loops are responsible for p53 oscillations. In the negative-feedback loop, p53* promotes production of Mdm2_cyt, which then enters the nucleus to induce degradation of p53*. In the positive-feedback loop, p53* induces Mdm2 to synthesize Mdm2_cyt, which promotes the translation of p53 mRNA to produce inactive p53.