References of "Barisic, Sandra"
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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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