Abstract
Apoptosis is a mechanism of programmed cell death in which cells engage in a controlled demolition and prepare to be digested without damaging their environment. In normal conditions, apoptosis is repressed until it is irreversibly induced by an appropriate signal. In adult organisms, apoptosis is a natural way to dispose of damaged cells and its disruption or excess is associated with cancer and autoimmune diseases. Apoptosis is regulated by a complex signaling network controlled by caspases, specialized enzymes that digest essential cellular components and promote the degradation of genomic DNA. In this work, we propose an effective description of the signaling network focused on caspase-3 as a readout of cell fate. We integrate intermediate network interactions into a nonlinear feedback function acting on caspase-3 and introduce the effect of pro-apoptotic stimuli and regulatory elements as a saturating activation function. We show that activation dynamics in the theory is similar to previously reported experimental results. We compute bifurcation diagrams and obtain cell fate maps describing how stimulus intensity and feedback strength affect cell survival and death fates. These fates overlap within a bistable region that depends on total caspase concentration, regulatory elements, and feedback nonlinearity. We study a strongly nonlinear regime to obtain analytical expressions for bifurcation curves and fate map boundaries. For a broad range of parameters, strong stimuli can induce an irreversible switch to the death fate. We use the theory to explore dynamical stimulation conditions and determine how cell fate depends on stimulation temporal patterns. This analysis predicts a critical relation between transient stimuli intensity and duration to trigger irreversible apoptosis. We derive an analytical expression for this critical relation, valid for short stimuli. Our description provides distinct predictions and offers a framework to study how this signaling network processes different stimuli to make a cell fate decision.
Highlights
Cells have intrinsic control mechanisms that can trigger cell death programs, such as apoptosis [1]
We show that activation dynamics in the theory is similar to previously reported experimental results
We propose an effective description of caspase dynamics that is endowed with bistability and irreversibility
Summary
Cells have intrinsic control mechanisms that can trigger cell death programs, such as apoptosis [1]. Effector caspases are considered the executioners of apoptosis: they cleave structural proteins, leading to a controlled cell demolition Both extrinsic and intrinsic stimuli can activate these enzymes, eliciting the sequence of events that trigger apoptosis. An extrinsic stimulus is the binding of an extracellular ligand, generally from the tumor necrosis factor family, to specific transmembrane death receptors [11] This promotes the assembly of a membrane bound signaling complex that cleaves and activates procaspase-8 [12]; see Fig. 1(a). The complexity of this network may obscure the key features that provide it with both tolerance to weak stimuli and commitment after apoptosis initiation, and how such features and stimulus intensity combine to determine a cell fate map It is unclear how such features regulate this fate decision in the presence of more complex, time-dependent stimuli. We use the theory to simulate dynamic stimulation conditions and predict cell fate outcomes in different scenarios
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