title: An integrative model links multiple inputs and signaling pathways to the onset of DNA synthesis in hepatocytes.
abstract: During liver regeneration, quiescent hepatocytes re-enter the cell cycle to proliferate and compensate for lost tissue. Multiple signals including hepatocyte growth factor, epidermal growth factor, tumor necrosis factor α, interleukin-6, insulin and transforming growth factor β orchestrate these responses and are integrated during the G(1) phase of the cell cycle. To investigate how these inputs influence DNA synthesis as a measure for proliferation, we established a large-scale integrated logical model connecting multiple signaling pathways and the cell cycle. We constructed our model based upon established literature knowledge, and successively improved and validated its structure using hepatocyte-specific literature as well as experimental DNA synthesis data. Model analyses showed that activation of the mitogen-activated protein kinase and phosphatidylinositol 3-kinase pathways was sufficient and necessary for triggering DNA synthesis. In addition, we identified key species in these pathways that mediate DNA replication. Our model predicted oncogenic mutations that were compared with the COSMIC database, and proposed intervention targets to block hepatocyte growth factor-induced DNA synthesis, which we validated experimentally. Our integrative approach demonstrates that, despite the complexity and size of the underlying interlaced network, logical modeling enables an integrative understanding of signaling-controlled proliferation at the cellular level, and thus can provide intervention strategies for distinct perturbation scenarios at various regulatory levels.
authors.affiliation: Max Planck Institute for Dynamics of Complex Technical Systems, Magdeburg, Germany.
authors.forename: Jérémy
authors.initials: J
authors.lastname: Huard
authors.forename: Stephanie
authors.initials: S
authors.lastname: Mueller
authors.forename: Ernst D
authors.initials: ED
authors.lastname: Gilles
authors.forename: Ursula
authors.initials: U
authors.lastname: Klingmüller
authors.forename: Steffen
authors.initials: S
authors.lastname: Klamt
mesh_terms: D000818:Animals; D002453:Cell Cycle / Q000502:physiology; D049109:Cell Proliferation; D004261:DNA Replication / Q000187:drug effects; D004815:Epidermal Growth Factor / Q000502:physiology; D017228:Hepatocyte Growth Factor / Q000502:physiology; D022781:Hepatocytes / Q000378:metabolism*; D007328:Insulin / Q000502:physiology; D015850:Interleukin-6 / Q000502:physiology; D008115:Liver Regeneration / Q000502:physiology; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D008954:Models, Biological; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D049490:Systems Biology; D016211:Transforming Growth Factor alpha / Q000502:physiology; D016212:Transforming Growth Factor beta / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology
chemical_list: D007328:Insulin; D015850:Interleukin-6; D016211:Transforming Growth Factor alpha; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; D004815:Epidermal Growth Factor; D017228:Hepatocyte Growth Factor; D019869:Phosphatidylinositol 3-Kinases; D020928:Mitogen-Activated Protein Kinases