BAX and SMAC regulate bistable properties of the apoptotic caspase system

Area of Science:

• Cellular Biology
• Biophysics
• Systems Biology

Background:

• Apoptosis is crucial for removing damaged cells, involving irreversible caspase activation regulated by a bistable switch.
• BAX and SMAC are key regulators of the caspase system, often implicated in diseases like cancer and neurodegeneration.

Purpose of the Study:

• To develop and validate a mathematical model describing how BAX and SMAC control the apoptotic switch.
• To investigate the specific roles of BAX and SMAC in regulating caspase activation dynamics.

Main Methods:

• Formulation of a mathematical model using ordinary differential equations based on existing literature.
• Utilizing simulations and bifurcation analysis to study model behavior.
• Experimental validation using cell culture with siRNA knockdowns and analysis of NCI-60 cell line data.

Main Results:

• The model accurately captures the interaction of BAX and SMAC with the caspase system.
• Both BAX and SMAC were found to regulate the time-delay and activation threshold of the apoptotic switch.
• BAX, but not SMAC, was predicted and experimentally confirmed to control the amplitude of the apoptotic switch.

Conclusions:

• A validated dynamic model of BAX and SMAC regulation of the apoptotic bistable switch has been established.
• The model provides insights into how BAX and SMAC influence caspase activation thresholds and dynamics.
• This framework can help distinguish drug responses in cell lines based on BAX expression levels.