Influence of the nuclear membrane, active transport, and cell shape on the Hes1 and p53-Mdm2 pathways: insights from...

Area of Science:

• Computational biology
• Mathematical modeling of biological systems
• Cellular signaling dynamics

Background:

• Intracellular signaling pathways often exhibit complex spatial dynamics and oscillations.
• Negative feedback loops are common in pathways like Hes1 and p53-Mdm2, implicated in cancer.
• Previous partial differential equation (PDE) models by Sturrock et al. studied these dynamics.

Purpose of the Study:

• To extend existing PDE models of intracellular signaling pathways.
• To incorporate a nuclear membrane and active transport (convection along microtubules) into the models.
• To investigate the impact of these extensions on oscillatory dynamics and parameter robustness.

Main Methods:

• Development of extended partial differential equation (PDE) models.
• Inclusion of a nuclear membrane and active transport mechanisms.
• Numerical simulations to explore parameter spaces and oscillatory behavior.
• Testing the p53-Mdm2 model with realistic cell geometries and drug effects.

Main Results:

• The extended models demonstrate sustained oscillatory dynamics within specific parameter ranges.
• Inclusion of the nuclear membrane and active transport broadens the parameter ranges that support oscillations, enhancing robustness.
• Simulations using realistic cell geometries align with experimental observations.
• The p53-Mdm2 model accurately predicts the effects of microtubule-disrupting and proteasome inhibitor drugs.

Conclusions:

• Enhanced PDE models incorporating nuclear transport and membranes improve the robustness of oscillatory dynamics in signaling pathways.
• These refined models provide a more accurate representation of in vivo cellular processes.
• The study validates the model's predictive power for drug effects in cancer-related signaling pathways.