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Cited by 29Liver physiology and pathologyGene Regulatory Network AnalysisMathematical Biology Tumor Growth

An integrative model links multiple inputs and signaling pathways to the onset of DNA synthesis in hepatocytes

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Huard, Jérémy, Mueller, Stephanie, Gilles, Ernst D., Klingmüller, Ursula, Klamt, Steffen·2012·The FEBS Journal
DOI 10.1111/j.1742-4658.2012.08572.xPMC PMC3466406
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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.

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Authors
Huard, J., Mueller, S., Gilles, E. D., Klingmüller, U., & Klamt, S.
Affiliations
  • Max Planck Institute for Dynamics of Complex Technical Systems (DE)
  • German Cancer Research Center (DE)
ORCID
Venue
The FEBS Journal
Publisher
Wiley
Published
2012-04-10
Volume
279
Issue
18
Pages
3290-3313
ISSN
  • 1742-464X (ISSN-L)
  • 1742-4658
DOI
10.1111/j.1742-4658.2012.08572.x
PMC
PMC3466406
OpenAlex
W1860244306
Cited by
29
References
7
Citations by year
2024: 1 · 2022: 2 · 2021: 2 · 2019: 2 · 2017: 4 · 2016: 6 · 2015: 3 · 2014: 4 · 2013: 3 · 2012: 2
FWCI
2.43
Type
journal article
Language
en
Open access
Licence
onlinelibrary.wiley.com/termsAndConditions#vor (vor)
Locations
  • FEBS Journal (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Max Planck Institute for Plasma Physics (submittedVersion)
  • MPG.PuRe (Max Planck Society) (submittedVersion)
Funders
Bundesministerium für Bildung und Forschung
Topics
  • Health Sciences › Medicine › Hepatology › Liver physiology and pathology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gene Regulatory Network Analysis
  • Physical Sciences › Mathematics › Modeling and Simulation › Mathematical Biology Tumor Growth
Keywords
liver regeneration, hepatocyte proliferation, DNA synthesis, cell cycle, G1 phase, signaling pathway integration, hepatocyte growth factor, MAPK signaling, phosphatidylinositol 3-kinase pathway, logical modeling, oncogenic mutations, intervention targets, hepatocyte quiescence
MeSH terms
Animals, Cell Cycle, DNA Replication, Epidermal Growth Factor, Insulin, Liver Regeneration, Models, Biological, Tumor Necrosis Factor-alpha, Signal Transduction, Interleukin-6, Transforming Growth Factor alpha, Transforming Growth Factor beta, Hepatocyte Growth Factor, Phosphatidylinositol 3-Kinases, Mitogen-Activated Protein Kinases, Hepatocytes, Cell Proliferation, Systems Biology, Mice

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