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  • 1
    Keywords: ADVANCED SOLID TUMORS ; PHASE-I ; REGULATORY NETWORKS ; receptor tyrosine kinase ; LIVER-REGENERATION ; FUNCTIONAL-ANALYSIS ; BIOLOGICAL NETWORKS ; NEGATIVE-FEEDBACK ; ORAL MEK INHIBITOR ; 3-PHOSPHOINOSITIDE-DEPENDENT PROTEIN KINASE-1
    Abstract: Signaling pathways are characterized by crosstalk, feedback and feedforward mechanisms giving rise to highly complex and cell-context specific signaling networks. Dissecting the underlying relations is crucial to predict the impact of targeted perturbations. However, a major challenge in identifying cell-context specific signaling networks is the enormous number of potentially possible interactions. Here, we report a novel hybrid mathematical modeling strategy to systematically unravel hepatocyte growth factor (HGF) stimulated phosphoinositide-3-kinase (PI3K) and mitogen activated protein kinase (MAPK) signaling, which critically contribute to liver regeneration. By combining time-resolved quantitative experimental data generated in primary mouse hepatocytes with interaction graph and ordinary differential equation modeling, we identify and experimentally validate a network structure that represents the experimental data best and indicates specific crosstalk mechanisms. Whereas the identified network is robust against single perturbations, combinatorial inhibition strategies are predicted that result in strong reduction of Akt and ERK activation. Thus, by capitalizing on the advantages of the two modeling approaches, we reduce the high combinatorial complexity and identify cell-context specific signaling networks.
    Type of Publication: Journal article published
    PubMed ID: 25905717
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  • 2
    Keywords: GROWTH-FACTOR ; SIGNALING PATHWAYS ; systems biology ; CELL-CYCLE PROGRESSION ; RETINOBLASTOMA PROTEIN ; PARTIAL-HEPATECTOMY ; LIVER-REGENERATION ; E2F TRANSCRIPTIONAL NETWORK ; S-PHASE ENTRY ; RESTRICTION POINT
    Abstract: Liver regeneration is a tightly controlled process mainly achieved by proliferation of usually quiescent hepatocytes. The specific molecular mechanisms ensuring cell division only in response to proliferative signals such as hepatocyte growth factor (HGF) are not fully understood. Here, we combined quantitative time-resolved analysis of primary mouse hepatocyte proliferation at the single cell and at the population level with mathematical modeling. We showed that numerous G1/S transition components are activated upon hepatocyte isolation whereas DNA replication only occurs upon additional HGF stimulation. In response to HGF, Cyclin:CDK complex formation was increased, p21 rather than p27 was regulated, and Rb expression was enhanced. Quantification of protein levels at the restriction point showed an excess of CDK2 over CDK4 and limiting amounts of the transcription factor E2F-1. Analysis with our mathematical model revealed that T160 phosphorylation of CDK2 correlated best with growth factor-dependent proliferation, which we validated experimentally on both the population and the single cell level. In conclusion, we identified CDK2 phosphorylation as a gate-keeping mechanism to maintain hepatocyte quiescence in the absence of HGF.
    Type of Publication: Journal article published
    PubMed ID: 25771250
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  • 3
    Keywords: GROWTH-FACTOR ; HEPATOCELLULAR-CARCINOMA ; BREAST-CANCER ; BUDDING YEAST ; systems biology ; PARTIAL-HEPATECTOMY ; LIVER-REGENERATION ; FUNCTIONAL-ANALYSIS ; MAMMALIAN-CELL CYCLE ; MOLECULAR INTERACTION MAP
    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 alpha, interleukin-6, insulin and transforming growth factor beta 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.
    Type of Publication: Journal article published
    PubMed ID: 22443451
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