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Survival and apoptotic pathways initiated by TNF‐α: Modeling and predictions
Author(s) -
Rangamani Padmini,
Sirovich Lawrence
Publication year - 2006
Publication title -
biotechnology and bioengineering
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.136
H-Index - 189
eISSN - 1097-0290
pISSN - 0006-3592
DOI - 10.1002/bit.21307
Subject(s) - apoptosis , dna fragmentation , fragmentation (computing) , transcription (linguistics) , dna damage , cell fate determination , microbiology and biotechnology , transcription factor , tumor necrosis factor alpha , cell survival , biology , cytosol , kinetics , dna , programmed cell death , cellular model , computational biology , chemistry , biophysics , biochemistry , genetics , physics , immunology , cell culture , enzyme , gene , ecology , linguistics , philosophy , quantum mechanics
We present a mathematical model which includes TNF‐α initiated survival and apoptotic cascades, as well as nuclear transcription of IκB. These pathways play a crucial role in deciding cell fate in response to inflammation and infection. Our model incorporates known specific protein–protein interactions as identified by experiments. Using these biochemical interactions, we develop a mathematical model of the NF‐κB‐mediated survival and caspase‐mediated apoptosis pathways. Using mass action kinetics, we follow the formation of the survival and late complexes as well as the dynamics of DNA fragmentation. The effect of TNF‐α concentration on DNA fragmentation is modeled and compares well with experiment. Nuclear transcription is also modeled phenomenologically by means of time lagged cytosolic concentrations. This results in transcription related concentrations undergoing under‐damped oscillations, in qualitative and quantitative agreement with experiment. Using a tumor cell as a hypothetical model, we explore the interplay between the components of the survival and apoptotic pathways. Results are presented which make predictions on the limits of cellular oscillations in terms of time delay, initial concentration ratios and other features of the model. The model also makes clear predictions on cell viability in terms of DNA damage within the framework of TNF‐α stimulus duration. Biotechnol. Bioeng. 2007; 97: 1216–1229. © 2006 Wiley Periodicals, Inc.