To investigate the regulation of NF-κB activity, a mathematical model of coupled ordinary differential equations was developed and analyzed. The model describes DNA damage-induced activation of NF-$&appa;B and quantitatively reproduces multiple experimental data sets. Analyzing the time-resolved regulation of NF-κB revealed regulatory mechanisms of DNA damage-dependent NF-κB signaling and allowed the evaluation of drug targets inhibiting NF-κB activity.
Further, the interplay of NF-κB and p53 signaling was investigated by developing a mathematical modeling framework to systematically identify interfaces between the NF-κB and p53 network. NF-κB signaling was perturbed and the resulting changes in single cell dynamics of p53 upon genotoxic stress were captured. By fitting a pool of subpopulation-specific ordinary differential equation models to the single cell data, one of the first quantitative p53 models reproducing the heterogeneous dynamics of p53 was developed. Based on the observed changes in p53 dynamics, the results of the modeling framework indicate that NF-κB signaling interferes with the activation and degradation of p53 as well as the degradation of its inhibitor Mdm2.
Taken together, the results in this work give new insights into the regulation of genotoxic NF-κB and p53 signaling and highlight the complexity of their crosstalk.
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