| Computational modeling and analysis of insulin induced eukaryotic translation initiation. | |
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MedLine Citation:
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PMID: 22102801 Owner: NLM Status: In-Data-Review |
Abstract/OtherAbstract:
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Insulin, the primary hormone regulating the level of glucose in the bloodstream, modulates a variety of cellular and enzymatic processes in normal and diseased cells. Insulin signals are processed by a complex network of biochemical interactions which ultimately induce gene expression programs or other processes such as translation initiation. Surprisingly, despite the wealth of literature on insulin signaling, the relative importance of the components linking insulin with translation initiation remains unclear. We addressed this question by developing and interrogating a family of mathematical models of insulin induced translation initiation. The insulin network was modeled using mass-action kinetics within an ordinary differential equation (ODE) framework. A family of model parameters was estimated, starting from an initial best fit parameter set, using 24 experimental data sets taken from literature. The residual between model simulations and each of the experimental constraints were simultaneously minimized using multiobjective optimization. Interrogation of the model population, using sensitivity and robustness analysis, identified an insulin-dependent switch that controlled translation initiation. Our analysis suggested that without insulin, a balance between the pro-initiation activity of the GTP-binding protein Rheb and anti-initiation activity of PTEN controlled basal initiation. On the other hand, in the presence of insulin a combination of PI3K and Rheb activity controlled inducible initiation, where PI3K was only critical in the presence of insulin. Other well known regulatory mechanisms governing insulin action, for example IRS-1 negative feedback, modulated the relative importance of PI3K and Rheb but did not fundamentally change the signal flow. |
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Authors:
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Joshua Lequieu; Anirikh Chakrabarti; Satyaprakash Nayak; Jeffrey D Varner |
Publication Detail:
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Type: Journal Article Date: 2011-11-10 |
Journal Detail:
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Title: PLoS computational biology Volume: 7 ISSN: 1553-7358 ISO Abbreviation: PLoS Comput. Biol. Publication Date: 2011 Nov |
Date Detail:
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Created Date: 2011-11-21 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 101238922 Medline TA: PLoS Comput Biol Country: United States |
Other Details:
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Languages: eng Pagination: e1002263 Citation Subset: IM |
Affiliation:
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School of Chemical and Biomolecular Engineering, Cornell University, Ithaca, New York, United States of America. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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