科研之友
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摘要
The cytokine tumor necrosis factor-alpha (TNF alpha) is one of the key factors during the priming phase of liver regeneration as well as in hepatocarcinogenesis. TNF alpha activates the nuclear factor k-light-chain-enhancer of activated B cells (NF kappa B) signaling pathway and contributes to the conversion of quiescent hepatocytes to activated hepatocytes that are able to proliferate in response to growth factor stimulation. Different mathematical models have been previously established for TNF alpha/NF kappa B signaling in the context of tumor cells. Combining these mathematical models with time-resolved measurements of expression and phosphorylation of INF alpha/NF kappa B pathway constituents in primary mouse hepatocytes revealed that an additional phosphorylation step of the NF kappa B isoform p65 has to be considered in the mathematical model in order to sufficiently describe the dynamics of pathway activation in the primary cells. Also, we addressed the role of basal protein turnover by experimentally measuring the degradation rate of pivotal players in the absence of INF alpha and including this information in the model. To elucidate the impact of variations in the protein degradation rates on INF alpha/NF kappa B signaling on the overall dynamic behavior we used global sensitivity analysis that accounts for parameter uncertainties and showed that degradation and translation of p65 had a major impact on the amplitude and the integral of p65 phosphorylation. Finally, our mathematical model of INF alpha/NF kappa B signaling was able to predict the time-course of the complex formation of p65 and of the inhibitor of NF kappa B (I kappa B) in primary mouse hepatocytes, which was experimentally verified. Hence, we here present a mathematical model for INF alpha/NF kappa B signaling in primary mouse hepatocytes that provides an important basis to quantitatively disentangle the complex interplay of multiple factors in liver regeneration and tumorigenesis.
- 出版日期2012
