Abstract
BackgroundThe decision pro- or contra apoptosis is complex, involves a number of different inputs, and is central for the homeostasis of an individual cell as well as for the maintenance and regeneration of the complete organism.ResultsThis study centers on Fas ligand (FasL)-mediated apoptosis, and a complex and internally strongly linked network is assembled around the central FasL-mediated apoptosis cascade. Different bioinformatical techniques are employed and different crosstalk possibilities including the integrin pathway are considered. This network is translated into a Boolean network (74 nodes, 108 edges). System stability is dynamically sampled and investigated using the software SQUAD. Testing a number of alternative crosstalk possibilities and networks we find that there are four stable system states, two states comprising cell survival and two states describing apoptosis by the intrinsic and the extrinsic pathways, respectively. The model is validated by comparing it to experimental data from kinetics of cytochrome c release and caspase activation in wildtype and Bid knockout cells grown on different substrates. Pathophysiological modifications such as input from cytomegalovirus proteins M36 and M45 again produces output behavior that well agrees with experimental data.ConclusionA network model for apoptosis and crosstalk in hepatocytes shows four different system states and reproduces a number of different conditions around apoptosis including effects of different growth substrates and viral infections. It produces semi-quantitative predictions on the activity of individual nodes, agreeing with experimental data. The model (SBML format) and all data are available for further predictions and development.
Highlights
The decision pro- or contra apoptosis is complex, involves a number of different inputs, and is central for the homeostasis of an individual cell as well as for the maintenance and regeneration of the complete organism
We established a comprehensive network of proteins involved in the apoptosis signaling of hepatocytes including different nodes around key pathways of apoptotic signaling as well as a number of proteins implicated in crosstalks
This study aims at integrating different apoptosis pathways and considering a number of different crosstalk possibilities in hepatocytes including different members of the integrin pathway
Summary
The decision pro- or contra apoptosis is complex, involves a number of different inputs, and is central for the homeostasis of an individual cell as well as for the maintenance and regeneration of the complete organism. A number of different studies already investigated and modeled different pathways implicated in liver cell apoptosis [1,2,3,4]. Hepatocytes use the so-called type II signaling pathway to apoptosis after stimulation with Fas ligand (FasL). In the presence of a collagen I monolayer, primary mouse hepatocytes switch to the type I signaling pathway in response to FasL. We inferred that this switch most likely occurs due to a crosstalk between the apoptosis and the collagen-integrin signaling pathways. This prompted us to conduct a systematic search for different system states in liver cells regarding apoptosis
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