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See detailIdentification of New IkappaBalpha Complexes by an Iterative Experimental and Mathematical Modeling Approach.
Konrath, Fabian; Witt, Johannes; Sauter, Thomas UL et al

in PLoS computational biology (2014), 10(3), 1003528

The transcription factor nuclear factor kappa-B (NFkappaB) is a key regulator of pro-inflammatory and pro-proliferative processes. Accordingly, uncontrolled NFkappaB activity may contribute to the ... [more ▼]

The transcription factor nuclear factor kappa-B (NFkappaB) is a key regulator of pro-inflammatory and pro-proliferative processes. Accordingly, uncontrolled NFkappaB activity may contribute to the development of severe diseases when the regulatory system is impaired. Since NFkappaB can be triggered by a huge variety of inflammatory, pro-and anti-apoptotic stimuli, its activation underlies a complex and tightly regulated signaling network that also includes multi-layered negative feedback mechanisms. Detailed understanding of this complex signaling network is mandatory to identify sensitive parameters that may serve as targets for therapeutic interventions. While many details about canonical and non-canonical NFkappaB activation have been investigated, less is known about cellular IkappaBalpha pools that may tune the cellular NFkappaB levels. IkappaBalpha has so far exclusively been described to exist in two different forms within the cell: stably bound to NFkappaB or, very transiently, as unbound protein. We created a detailed mathematical model to quantitatively capture and analyze the time-resolved network behavior. By iterative refinement with numerous biological experiments, we yielded a highly identifiable model with superior predictive power which led to the hypothesis of an NFkappaB-lacking IkappaBalpha complex that contains stabilizing IKK subunits. We provide evidence that other but canonical pathways exist that may affect the cellular IkappaBalpha status. This additional IkappaBalpha:IKKgamma complex revealed may serve as storage for the inhibitor to antagonize undesired NFkappaB activation under physiological and pathophysiological conditions. [less ▲]

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See detailAnalysing the role of UVB-induced translational inhibition and PP2Ac deactivation in NF-kappaB signalling using a minimal mathematical model.
Witt, Johannes; Konrath, Fabian; Sawodny, Oliver et al

in PLoS ONE (2012), 7(7), 40274

Activation of nuclear factor kappaB (NF-kappaB) by interleukin-1beta (IL-1) usually results in an anti-apoptotic activity that is rapidly terminated by a negative feedback loop involving NF-kappaB ... [more ▼]

Activation of nuclear factor kappaB (NF-kappaB) by interleukin-1beta (IL-1) usually results in an anti-apoptotic activity that is rapidly terminated by a negative feedback loop involving NF-kappaB dependent resynthesis of its own inhibitor IkappaBalpha. However, apoptosis induced by ultraviolet B radiation (UVB) is not attenuated, but significantly enhanced by co-stimulation with IL-1 in human epithelial cells. Under these conditions NF-kappaB remains constitutively active and turns into a pro-apoptotic factor by selectively repressing anti-apoptotic genes. Two different mechanisms have been separately proposed to explain UV-induced lack of IkappaBalpha recurrence: global translational inhibition as well as deactivation of the Ser/Thr phosphatase PP2Ac. Using mathematical modelling, we show that the systems behaviour requires a combination of both mechanisms, and we quantify their contribution in different settings. A mathematical model including both mechanisms is developed and fitted to various experimental data sets. A comparison of the model results and predictions with model variants lacking one of the mechanisms shows that both mechanisms are present in our experimental setting. The model is successfully validated by the prediction of independent data. Weak constitutive IKKbeta phosphorylation is shown to be a decisive process in IkappaBalpha degradation induced by UVB stimulation alone, but irrelevant for (co-)stimulations with IL-1. In silico knockout experiments show that translational inhibition is predominantly responsible for lack of IkappaBalpha recurrence following IL-1+UVB stimulation. In case of UVB stimulation alone, cooperation of both processes causes the observed decrease of IkappaBalpha. This shows that the processes leading to activation of transcription factor NF-kappaB upon stimulation with ultraviolet B radiation with and without interleukin-1 costimulation are more complex than previously thought, involving both a cross talk of UVB induced translational inhibition and PP2Ac deactivation. The importance of each of the mechanisms depends on the specific cellular setting. [less ▲]

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See detailModeling time delay in the NFkappaB signaling pathway following low dose IL-1 stimulation.
Witt, Johannes; Barisic, Sandra; Sawodny, Oliver et al

in EURASIP Journal on Bioinformatics & Systems Biology (2011), 2011(1), 3

Stimulation of human epithelial cells with IL-1 (10 ng/ml) + UVB radiation results in sustained NFkappaB activation caused by continuous IKKbeta phosphorylation. We have recently published a strictly ... [more ▼]

Stimulation of human epithelial cells with IL-1 (10 ng/ml) + UVB radiation results in sustained NFkappaB activation caused by continuous IKKbeta phosphorylation. We have recently published a strictly reduced ordinary differential equation model elucidating the involved mechanisms. Here, we compare model extensions for low IL-1 doses (0.5 ng/ml), where delayed IKKbeta phosphorylation is observed. The extended model including a positive regulatory element, most likely auto-ubiquitination of TRAF6, reproduces the observed experimental data most convincingly. The extension is shown to be consistent with the original model and contains very sensitive processes which may serve as potential intervention targets. [less ▲]

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See detailMechanism of PP2A-mediated IKK beta dephosphorylation: a systems biological approach.
Witt, Johannes; Barisic, Sandra; Schumann, Eva et al

in BMC Systems Biology (2009), 3

BACKGROUND: Biological effects of nuclear factor-kappaB (NF kappaB) can differ tremendously depending on the cellular context. For example, NF kappaB induced by interleukin-1 (IL-1) is converted from an ... [more ▼]

BACKGROUND: Biological effects of nuclear factor-kappaB (NF kappaB) can differ tremendously depending on the cellular context. For example, NF kappaB induced by interleukin-1 (IL-1) is converted from an inhibitor of death receptor induced apoptosis into a promoter of ultraviolet-B radiation (UVB)-induced apoptosis. This conversion requires prolonged NF kappaB activation and is facilitated by IL-1 + UVB-induced abrogation of the negative feedback loop for NF kappaB, involving a lack of inhibitor of kappaB (I kappaB alpha) protein reappearance. Permanent activation of the upstream kinase IKK beta results from UVB-induced inhibition of the catalytic subunit of Ser-Thr phosphatase PP2A (PP2Ac), leading to immediate phosphorylation and degradation of newly synthesized I kappaB alpha. RESULTS: To investigate the mechanism underlying the general PP2A-mediated tuning of IKK beta phosphorylation upon IL-1 stimulation, we have developed a strictly reduced mathematical model based on ordinary differential equations which includes the essential processes concerning the IL-1 receptor, IKK beta and PP2A. Combining experimental and modelling approaches we demonstrate that constitutively active, but not post-stimulation activated PP2A, tunes out IKK beta phosphorylation thus allowing for I kappaB alpha resynthesis in response to IL-1. Identifiability analysis and determination of confidence intervals reveal that the model allows reliable predictions regarding the dynamics of PP2A deactivation and IKK beta phosphorylation. Additionally, scenario analysis is used to scrutinize several hypotheses regarding the mode of UVB-induced PP2Ac inhibition. The model suggests that down regulation of PP2Ac activity, which results in prevention of I kappaB alpha reappearance, is not a direct UVB action but requires instrumentality. CONCLUSION: The model developed here can be used as a reliable building block of larger NF kappa B models and offers comprehensive simplification potential for future modeling of NF kappa B signaling. It gives more insight into the newly discovered mechanisms for IKK deactivation and allows for substantiated predictions and investigation of different hypotheses. The evidence of constitutive activity of PP2Ac at the IKK complex provides new insights into the feedback regulation of NF kappa B, which is crucial for the development of new anti-cancer strategies. [less ▲]

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See detailModeling and Analysis of UVB Influence on IL-1 induced NF-kappaB Signaling
Witt, Johannes; Husser, Sebastian; Kulms, Dagmar et al

in Proceedings of the FOSBE, September 9-12, Stuttgart, Germany (2007)

Enhancement of UVB-induced apoptosis has recently been reported upon co-stimulation of cells with IL-1. The phenomenon has been shown to be NF-kappaB dependent and coincides with a sustained absence of ... [more ▼]

Enhancement of UVB-induced apoptosis has recently been reported upon co-stimulation of cells with IL-1. The phenomenon has been shown to be NF-kappaB dependent and coincides with a sustained absence of the inhibitor of NF-kappaB, IkappaBalpha. The exact mechanisms are the subject of present research. In order to investigate the behavior of IkappaBalpha, a mathematical model for the IL-1 receptor is developed based on ordinary differential equations. It is coupled with an existing NF-kappaB signaling module and parameterized using experimental and literature data. The model provides a more realistic input for the NF-kappaB module and is suitable for fitting the experimental data of IkappaBalpha following IL-1 stimulation. It is used to test and reject the hypothesis that the sustained absence of IkappaBalpha upon IL-1+UVB stimulation is due to an altered internalization behavior of the IL-1 receptor. [less ▲]

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