1,721,182 research outputs found
Experimental design in systems biology, based on parameter sensitivity analysis using a Monte Carlo method: A case study for the TNF alpha-mediated NF-kappa B signal transduction pathway
No full textMathematical modeling and dynamic simulation of signal transduction pathways is a central theme in systems biology and is increasingly attracting attention in the postgenomic era. The estimation of model parameters from experimental data remains a bottleneck for a major breakthrough in this area. This study's aim is to introduce a new strategy for experimental design based on parameter sensitivity analysis. The approach identifies key parameters/variables in a signal transduction pathway model and can thereby provide experimental biologists with guidance on which proteins to consider for measurement. The article focuses on applying this approach to the TNFalpha-mediated NF-kappaB pathway, which plays an important role in immunity and inflammation and in the control of cell proliferation, differentiation, and apoptosis. A mathematical model of this pathway is proposed, and the sensitivity analysis of model parameters is illustrated for this model by employing the Monte Carlo method over a broad range of parameter values
System-level investigations into the functional role of RKIP in the Ras-Raf-MEK-ERK signal transduction pathway
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Modeling and analysis of two feedback loop dynamics in Ras/Raf-1/MEK/ERK signaling pathway
No full textA hidden oncogenic positive feedback loop caused by crosstalk between Wnt and ERK Pathways
No full textThe Wnt and the extracellular signal regulated-kinase (ERK) pathways are both involved in the pathogenesis of various kinds of cancers. Recently, the existence of crosstalk between Wnt and ERK pathways was reported. Gathering all reported results, we have discovered a positive feedback loop embedded in the crosstalk between the Wnt and ERK pathways. We have developed a plausible model that represents the role of this hidden positive feedback loop in the Wnt/ERK pathway crosstalk based on the integration of experimental reports and employing established basic mathematical models of each pathway. Our analysis shows that the positive feedback loop can generate bistability in both the Wnt and ERK signaling pathways, and this prediction was further validated by experiments. In particular, using the commonly accepted assumption that mutations in signaling proteins contribute to cancerogenesis, we have found two conditions through which mutations could evoke an irreversible response leading to a sustained activation of both pathways. One condition is enhanced production of beta-catenin, the other is a reduction of the velocity of MAP kinase phosphatase(s). This enables that high activities of Wnt and ERK pathways are maintained even without a persistent extracellular signal. Thus, our study adds a novel aspect to the molecular mechanisms of carcinogenesis by showing that mutational changes in individual proteins can cause fundamental functional changes well beyond the pathway they function in by a positive feedback loop embedded in crosstalk. Thus, crosstalk between signaling pathways provides a vehicle through which mutations of individual components can affect properties of the system at a larger scale
Mathematical Modeling of the influence of RKIP on the ERK signaling pathway
No full textThis paper investigates the influence of the Raf Kinase Inhibitor Protein (RKIP) on the Extracellular signal Regulated Kinase (ERK) signaling pathway through mathematical modeling and simulation. Using nonlinear ordinary differential equations to represent biochemical reactions in the pathway, we suggest a technique for parameter estimation, utilizing time series data of proteins involved in the signaling pathway. The mathematical model allows the simulation the sensitivity of the ERK pathway to variations of initial RKIP and ERK-PP (phosphorylated ERK) concentrations along with time. Throughout the simulation study, we can qualitatively validate the proposed mathematical model compared with experimental results
Analysis of the mechanisms through which K-RASG12V and K-RASG13D regulate the proliferation and cell death in cells HT-29
Full text linkCodon 12 and codon 13 mutations in K-RAS differentially affect colorectal carcinoma cells
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