A Computational Model of Mammalian Cell Cycle Using Petri Nets

The mammalian cell cycle is regulated by Cyclin-dependent kinases (Cdks) whose activity is strictly controlled by the physical association with regulatory subunits known as Cyclins and by the phosphorylation and dephosphorylation of catalytic subunits. In higher eukaryotes, Cdk2-cyclin A and Cdc2-cyclin B (MPF) are needed for the maintenance and progression of the S phase and mitosis, respectively [5]. To activate MPF, the Cdk-activating kinase (CAK) phosphorylates Thr160 on a Cdc2 subunit during the S phase. During the S and G2 phases, Thr14 and Tyr15 on Cdc2 are phosphorylated to inhibit the kinase activity, and they are dephosphorylated to activate MPF with the onset of mitosis. Therefore, the phosphorylation and dephosphorylation of Thr14 and Tyr15 are required to accurately control the MPF activation [6]. In eukaryotic cells, Wee1/Myt1 and Cdc25 are major enzymes that regulate, respectively, the phosphorylation and dephosphorylation of Thr14 and/or Tyr15 on Cdc2 [1]. The destruction of Cyclin B by Ubiquitin-dependent proteolysis is essential for the exit from mitosis [7]. Petri Nets (PNs) have been developed in the field of computer science; they have a standard graphical representation, which is easy to interpret and use to define models [2]. It is easy to embellish the model in a standardized format of PNs [9]. Therefore, it is very helpful for us to understand complicated reaction systems by using PNs when the behaviors of molecular interactions and kinetics in the cells are modeled.