A mathematical treatment of the impact of p53 signalling on the expression of the transcription factor E2F in the CycE/Cdk2 subsystem in cancerous cells

Complex networks of proteins and genes control cell growth until mitosis. These components play crucial roles in determining the characteristics and timing of each reaction in the cell. A family of cyclins and cyclin-dependent kinases regulates the progression of the cell from one stage to the next, while certain inhibitors regulate cell proliferation, significantly impacting this process. We examine the impact of p53 protein production in the cyclin E/cyclin-dependent kinase 2 (CycE/CDK2) subsystem. Although the precise functioning of the p53 protein is not fully understood, it is known to exhibit pulsatile behaviour, triggered in response to DNA damage. Consequently, the expression of the p53 protein within the cell system increases with the severity of DNA damage. Similarly, levels of CycE/CDK2 are substantially elevated in instances of DNA damage.

To investigate this subsystem, we have developed a mathematical model of the CycE/CDK2 subsystem, presented as non-linear ordinary differential equations. Our primary aim is to determine the conditions that could theoretically result in tumorigenesis. We conduct a dynamical systems analysis to investigate the presence of stable limit cycles, which indicate the standard operational states of cells. Our investigation reveals the levels of p53 protein at which the cell can correct defects, undergo apoptosis, or enter quiescence, and where the system exhibits a Hopf-bifurcation (limit cycles). This is the novelty of our study, as previous research has primarily focused on numerical simulations.

Using MATLAB simulations, we produced various results in response to different expressions and concentrations of the p53 protein, allowing us to assess its influence on malignant cells. By altering the concentration of protein p53, we ascertain the specific cellular circumstances that facilitate its natural growth, self-correction in the presence of defective activity, and entry into a state of quiescence.

This investigation is motivated by the significant role of oscillations in driving, controlling, and managing the cellular oversight machinery. These aspects are incorporated into developing a mathematical model that emulates cellular operations. From this research, we establish that E2F is a critical target to mitigate oncogenic activity, achievable by managing the pulsatile behaviour of the inhibitor p53 or inhibiting its production process within the cell machinery.