A Computer‐Based Model for the Regulation of Mitogen Activated Protein Kinase (MAPK) Activation

Aksan, Isil; Kurnaz, M. Levent

doi:10.1081/rrs-120025203

Cited by 17 publications

(17 citation statements)

References 39 publications

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“…The base model of ligand-induced MAPK activation has been previously published (Aksan and Kurnaz, 2003). In this model, transient activation of the MAPK pathway (maximal activation within 5 min, returning to basal levels thereafter) is achieved by stimulating the cell with 100 nM EGF.…”

Section: Resultsmentioning

confidence: 99%

“…The reactions upstream of these events have been previously described in great detail (Aksan and Kurnaz, 2003; http://chemphys.phys.boun.edu.tr/biochem/).…”

Section: Ab Complexmentioning

confidence: 99%

“…In order for the system to return to the basal level, they need to be downregulated by dephosphorylation. These steps have been explicitly included in the MAPK model as reverse reactions (Aksan and Kurnaz, 2003).…”

Section: Reactions and Biochemical Parametersmentioning

confidence: 99%

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Kinetic analysis of RSK2 and Elk‐1 interaction on the serum response element and implications for cellular engineering

Kurnaz

2004

Biotech & Bioengineering

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Immediate early gene activation upon mitogenic activation occurs through the serum response element (SRE), which makes the delineation of the upstream pathways a powerful means to engineer cellular responses. The malfunctioning of this system leads to a variety of disorders, ranging from neurological disorders such as Coffin-Lowry syndrome (RSK2 mutations) to cancer (c-fos mutations). We therefore investigated the SRE activation mechanism in a typical mammalian cell. Mitogenic signaling uses the mitogen-activated protein kinase (MAPK) module through increased binding of the ternary complex factor (TCF), such as Elk-1, to the promoter DNA (the SRE element) and subsequent transcriptional activation, as well as through activation of a histone kinase, such as the MAPK-activated protein kinase (MAPKAP-K) ribosomal S6 kinase (RSK2). This computational model uses the biochemical simulation environment GEPASI 3.30 to investigate three major models of interaction for Elk-1 and RSK2, and to study the effect of histone acetyl transferase (HAT) recruitment in each of these models on the local chromatin modifications in the presence and absence of MAPK activation. We show that the quickest response on the chromatin can be achieved in the presence of a preformed complex of RSK2, Elk-1 and HAT, with HAT being activated upon dissociation from the complex upon activation of the MAPK cascade. This study presents critical components in the pathway that can be targeted for engineering of specific inhibitors or activators of the system.

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Section: Resultsmentioning

confidence: 99%

“…The reactions upstream of these events have been previously described in great detail (Aksan and Kurnaz, 2003; http://chemphys.phys.boun.edu.tr/biochem/).…”

Section: Ab Complexmentioning

confidence: 99%

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Kinetic analysis of RSK2 and Elk‐1 interaction on the serum response element and implications for cellular engineering

Kurnaz

2004

Biotech & Bioengineering

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“…Therefore, PC12 cells were next transfected with mouse Pea3, either in the presence or absence of Epidermal Growth Factor (EGF). In contrast to Nerve Growth Factor (NGF), which results in sustained MAPK activation and neuronal differentiation, EGF is known to lead to proliferation in these cells through transient activation of the MAPK pathway (Marshall, 1995; Aksan and Kurnaz, 2003). Although EGF is not sufficient to drive differentiation of PC12 cells on its own, in combination with exogenous mPea3 it was seen to enhance long axonal projections ( Figures 1D,E ).…”

Section: Resultsmentioning

confidence: 99%

Pea3 transcription factor promotes neurite outgrowth

Kandemir

Çağlayan

Hausott

et al. 2014

Front. Mol. Neurosci.

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Pea3 subfamily of E–twenty six transcription factors consist of three major -exhibit branching morphogenesis, the function of Pea3 family in nervous system development and regeneration is only beginning to unfold. In this study, we provide evidence that Pea3 can directs neurite extension and axonal outgrowth in different model systems, and that Serine 90 is important for this function. We have also identified neurofilament-L and neurofilament-M as two putative novel targets for Pea3.

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“…In order for these cells to differentiate, MAP kinase cascade activation must be sustained. Many different kinetic models have been developed to characterize the behavior of PC12 cells in response to neurotrophin stimulation24–27 and these models were used as a starting point for this study. Additionally, the concentrations of the different proteins that make up the MAP kinase signaling cascade are known for the PC12 cell line, and this information could be used to estimate the concentrations of the signaling cascade components in stem cells or embryonic stem cell–derived neural progenitor cells (ESNPCs).…”

Section: Introductionmentioning

confidence: 99%

Correction

2009

Tissue Engineering Part C: Methods

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The goal of this study was to develop a kinetic analysis that could predict the behavior of embryonic stem cell-derived neural progenitor cells (ESNPCs) in response to treatment with neurotrophin-3 (NT-3). Previous studies have shown that NT-3 activates the mitogen-activated protein (MAP) kinase cascade in embryonic stem cells and promotes differentiation of ESNPCs into neurons. MAP kinase activation after NT-3 stimulation was confirmed experimentally, and a kinetic analysis was developed using rate constants obtained from the literature. Concentrations of select signaling components were estimated for ESNPCs using real-time reverse transcription polymerase chain reaction by comparing mRNA levels to those of cell types with known protein concentrations. This assumption was validated using Western blots, and incorporated into the analysis. This analysis was used to predict the minimum NT-3 concentration necessary to promote neuronal differentiation of ESNPCs based on the activation of MAP kinase. These predictions were then tested experimentally to confirm the validity of the analysis. Finally, expression of the transcription factor mammalian achate schute homolog 1 and beta-tubulin III (an early neuronal marker) was examined in response to the different NT-3 doses to confirm the link between MAP kinase activation and neuronal differentiation. Overall, this study provides insight into the kinetics of the intracellular processes that promote ESNPC differentiation to neurons.

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A Computer‐Based Model for the Regulation of Mitogen Activated Protein Kinase (MAPK) Activation

Cited by 17 publications

References 39 publications

Kinetic analysis of RSK2 and Elk‐1 interaction on the serum response element and implications for cellular engineering

Kinetic analysis of RSK2 and Elk‐1 interaction on the serum response element and implications for cellular engineering

Pea3 transcription factor promotes neurite outgrowth

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