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Signaling perturbations induced by invading H. pylori proteins in the host epithelial cells: a mathematical modeling approach.

ABSTRACT: Helicobacter pylori (H. pylori), a gram-negative bacterium, infects the stomach of approximately 50% of the world population. H. pylori infection is a risk factor for developing chronic gastric ulcers and gastric cancer. The bacteria produce two main cytotoxic proteins: Vacuolating cytotoxin A (VacA) and Cytotoxin-Associated gene A (CagA). When these proteins enter the host cell they interfere with the host MAP Kinase and Apoptosis signaling pathways leading to aberrant cell growth and premature apoptosis. The present study expanded existing quantitative models of the MAP Kinase and Apoptosis signaling pathways to take into account the protein interactions across species using the CellDesigner tool. The resulting network contained hundreds of differential equations in which the coefficients for the biochemical rate constants were estimated from previously published studies. The effect of VacA and CagA on the function of this network were simulated by increasing levels of bacterial load. Simulations showed that increasing bacterial load affected the MAP Kinase signaling in a dose dependant manner. The introduction of CagA decreased the activation time of mapK signaling and extended activation indefinitely despite normal cellular activity to deactivate the protein. Introduction of VacA produced a similar response in the apoptosis pathway. Bacterial load activated both pathways even in the absence of external stimulation. Time course of emergence of transcription factors associated with cell division and cell death predicted by our simulation showed close agreement with that determined from a publicly accessible microarray data set of H. pylori infected stomach epithelium. The quantitative model presented in this study lays the foundation for investigating the affects of single nucleotide polymorphisms (SNPs) on the efficiency of drug treatment.

SUBMITTER: Dampier W

PROVIDER: S-EPMC2080843 | biostudies-literature | 2007 Sep

REPOSITORIES: biostudies-literature

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Signaling perturbations induced by invading H. pylori proteins in the host epithelial cells: a mathematical modeling approach.

Dampier William W Tozeren Aydin A

Journal of theoretical biology 20070318 1

Helicobacter pylori (H. pylori), a gram-negative bacterium, infects the stomach of approximately 50% of the world population. H. pylori infection is a risk factor for developing chronic gastric ulcers and gastric cancer. The bacteria produce two main cytotoxic proteins: Vacuolating cytotoxin A (VacA) and Cytotoxin-Associated gene A (CagA). When these proteins enter the host cell they interfere with the host MAP Kinase and Apoptosis signaling pathways leading to aberrant cell growth and premature ...[more]

PMID: 17559886

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Project description:Under oxidative and electrophilic stresses, cells launch an NRF2-mediated transcriptional antioxidant program. The activation of NRF2 depends on a redox sensor, KEAP1, which promotes the ubiquitination and degradation of NRF2. While a great deal has been learned about this duo, its quantitative signaling properties are largely unexplored. Here we examined these properties, including half-life, maximal activation, and response steepness (ultrasensitivity) of NRF2, through mathematical modeling. The models describe the binding of KEAP1 and NRF2 via ETGE and DLG motifs, NRF2 production, KEAP1-dependent and independent NRF2 degradation, and perturbations by different classes of NRF2 activators. Simulations revealed at the basal condition, NRF2 is sequestered by KEAP1 and the KEAP1-NRF2 complex is distributed comparably in an ETGE-bound (open) state and an ETGE and DLG dual-bound (closed) state. When two-step ETGE binding is considered, class I-V, electrophilic NRF2 activators shift the balance to a closed state incompetent to degrade NRF2, while the open and closed KEAP1-NRF2 complexes transition from operating in cycle mode to equilibrium mode. Ultrasensitive NRF2 activation (a steep rise of free NRF2) can occur when NRF2 nearly saturates KEAP1. The ultrasensitivity results from zero-order degradation through DLG binding and protein sequestration through ETGE binding. Optimal abundances of cytosolic and nuclear KEAP1 exist to maximize ultrasensitivity. These response characteristics do not require disruption of DLG binding as suggested by the hinge-latch hypothesis. In comparison, class VI NRF2 activators cause a shift to the open KEAP1-NRF2 complex and ultimately its complete dissociation, resulting in a fast release of NRF2 followed by stabilization. However, ultrasensitivity is lost due to decreasing free KEAP1 abundance. In summary, by simulating the dual role of KEAP1, i.e., sequestering and promoting degradation of NRF2, our modeling provides novel quantitative insights into NRF2 activation, which may help design novel NRF2 modulators and understand the oxidative actions of environmental stressors.

Dataset Information

Signaling perturbations induced by invading H. pylori proteins in the host epithelial cells: a mathematical modeling approach.

Publications

Signaling perturbations induced by invading H. pylori proteins in the host epithelial cells: a mathematical modeling approach.

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