From experiments to model and back: activity flow in the apoptotic network
Departamento de Física, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires Instituto de Física de Buenos Aires, CONICET
Apoptosis, a form of programmed cell death central to all multicellular organisms, plays a key role during organism development and is often misregulated in cancer. Devising a single model applicable to distinct stimuli and conditions has been limited by lack of robust observables. Indeed, previous numerical models have been tailored to fit experimental datasets in restricted scenarios, failing to predict response to different stimuli. Using an anisotropy-based FRET sensor array, we obtained a comprehensive dataset in which the activity of three caspases simultaneously upon intrinsic or extrinsic stimulation. We modeled the time between maximum activity of intrinsic, extrinsic and effector caspases, a robust observable of network dynamics, to create the first integrated Apoptotic Reaction Model (ARM). Observing how effector caspases reach maximum activity first irrespective of stimuli used, led us to identify and incorporate missing feedback into a successful model for extrinsic stimulation. By simulating different recently performed experiments, we corroborated that ARM adequately describes them. This integrated model provides further insight into the indispensable feedback from effector caspase to initiator caspases.