Fig. 4
Strong positive feedback significantly alters the dose response of p53 dynamics, especially rendering unique p53 transitional dynamics. A Pathway diagrams with Type 1- or Type 2-positive feedback in addition to the central p53-Mdm2 negative feedback. PF denotes the positive feedback gene that is a transcriptional target of p53. B, C Dose response of p53 dynamics under B weak positive feedback strength and C strong positive feedback strength (left panel: Type 1; right panel: Type 2). D Correlation of the different p53 dynamic phenotypes with the values of γf (the degradation rate of PF) and Kf (the Michaelis parameter for p53-induced PF upregulation). E Dynamics of Mdm2 (left panel) and PF (right panel) resulted from the Type 1-positive feedback under increasing concentrations of Nutlin-3a. The drug concentrations are color-coded as those in B, C. F Correlation analysis of the time (upper panel) and p53 level (lower panel) at the turning point of p53 dynamics under intermediate concentrations of Nutlin-3a showed a significant dependence on kmp (the rate constant of Mdm2-mediated p53 degradation). G Comparison of the expression levels of PTEN, p53, and Mdm2 in the five selected cancer cell lines after 24-h treatment of the indicated Nutlin-3a or 5-FU concentration. H p53 expression levels under PTEN knockdown (siPTEN) vs. control in A549 (left panel) and U-2 OS (right panel) cells after a 24-h treatment of the indicated Nutlin-3a or 5-FU concentration