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dc.titleComputational analysis reveals the coupling between bistability and the sign of a feedback loop in a TGF-?1 activation model
dc.contributor.authorLi, H
dc.contributor.authorVenkatraman, L
dc.contributor.authorNarmada, B.C
dc.contributor.authorWhite, J.K
dc.contributor.authorYu, H
dc.contributor.authorTucker-Kellogg, L.
dc.identifier.citationLi, H, Venkatraman, L, Narmada, B.C, White, J.K, Yu, H, Tucker-Kellogg, L. (2017). Computational analysis reveals the coupling between bistability and the sign of a feedback loop in a TGF-?1 activation model. BMC Systems Biology 11 : 136. ScholarBank@NUS Repository.
dc.description.abstractBackground: Bistable behaviors are prevalent in cell signaling and can be modeled by ordinary differential equations (ODEs) with kinetic parameters. A bistable switch has recently been found to regulate the activation of transforming growth factor-?1 (TGF-?1) in the context of liver fibrosis, and an ordinary differential equation (ODE) model was published showing that the net activation of TGF-?1 depends on the balance between two antagonistic sub-pathways. Results: Through modeling the effects of perturbations that affect both sub-pathways, we revealed that bistability is coupled with the signs of feedback loops in the model. We extended the model to include calcium and Krüppel-like factor 2 (KLF2), both regulators of Thrombospondin-1 (TSP1) and Plasmin (PLS). Increased levels of extracellular calcium, which alters the TSP1-PLS balance, would cause high levels of TGF-?1, resembling a fibrotic state. KLF2, which suppresses production of TSP1 and plasminogen activator inhibitor-1 (PAI1), would eradicate bistability and preclude the fibrotic steady-state. Finally, the loop PLS - TGF-?1 - PAI1 had previously been reported as negative feedback, but the model suggested a stronger indirect effect of PLS down-regulating PAI1 to produce positive (double-negative) feedback in a fibrotic state. Further simulations showed that activation of KLF2 was able to restore negative feedback in the PLS - TGF-?1 - PAI1 loop. Conclusions: Using the TGF-?1 activation model as a case study, we showed that external factors such as calcium or KLF2 can induce or eradicate bistability, accompanied by a switch in the sign of a feedback loop (PLS - TGF-?1 - PAI1) in the model. The coupling between bistability and positive/negative feedback suggests an alternative way of characterizing a dynamical system and its biological implications. © 2017 The Author(s).
dc.sourceUnpaywall 20200831
dc.subjecttransforming growth factor beta1
dc.subjectbiological model
dc.subjectphysiological feedback
dc.subjectsignal transduction
dc.subjectFeedback, Physiological
dc.subjectModels, Biological
dc.subjectSignal Transduction
dc.subjectTransforming Growth Factor beta1
dc.contributor.departmentMECHANOBIOLOGY INSTITUTE
dc.contributor.departmentDEPT OF PHYSIOLOGY
dc.contributor.departmentDUKE-NUS MEDICAL SCHOOL
dc.description.sourcetitleBMC Systems Biology
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