Hybrid Modeling of the p53 and Akt associated Gene Regulatory Network

Abstract

p53 is known as a genome guardian gene as it bears a putative function in the DNA damage associated gene regulatory networks (GRNs). These GRNs

integrate many upstream signals to up-regulate p53 and in turn p53 either up- regulates or down- regulates many downstream signals. A formal model was

proposed and analyzed using several approaches like model checking, kinetic logic and hybrid modeling. Initially, the GRN comprising of the entities p53, Akt and Mdm2c and Mdm2n was modeled using kinetic logic of Ren ́e Thomas. The logical parameters for the qualitative model were infered using the model checking approach implemented in SMBioNet. The qualitative model predicts a stable state and cycles representing the over expression and homeostasis of the entities, respectively. The model also predicts the bifurcation states, which cause divergence from the normal cyclic behaviours towards the stable state. We also computed the conditions in the form of delay constraints for the existence of cycles using hybrid model checking. This model increases the understanding of p53 regulatory mechanism through which the system diverts from normal state to disease state. Thus, the presented model clearly depicts the significance of Akt mediated regulation of p53 by revealing the dynamics involved in the network.