Reference : Optimization of stress response through the nuclear receptor-mediated cortisol signal...
Scientific journals : Article
Life sciences : Biochemistry, biophysics & molecular biology
Optimization of stress response through the nuclear receptor-mediated cortisol signalling network
Kolodkin, Alexey* mailto [University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > >]
Sahin, Nilgun* mailto [VU University Amsterdam > Molecular Cell Physiology]
Phillips, Anna mailto [University of Surrey > Faculty of Health and Medical Sciences, Centre for Toxicology]
Hood, Steve R. mailto [GlaxoSmithKline]
Bruggeman, Frank J. mailto [Netherlands Institute of Systems Biology > Regulatory Networks Group]
Westerhoff, Hans V. mailto [University of Manchester > Manchester Centre for Integrative Systems Biology]
Plant, Nick mailto [University of Surrey > Faculty of Health and Medical Sciences, Centre for Toxicology]
* These authors have contributed equally to this work.
Nature Communications
Nature Publishing Group
Yes (verified by ORBilu)
United Kingdom
[en] systems biology ; nuclear receptors ; stress response ; kinetic modeling ; design principles ; glucocorticoid receptors (GR) ; pregnane X-receptor (PXR) ; cortisol ; signalling network
[en] It is an accepted paradigm that extended stress predisposes an individual to pathophysiology. However, the biological adaptations to minimize this risk are poorly understood. Using a computational model based upon realistic kinetic parameters we are able to reproduce the interaction of the stress hormone cortisol with its two nuclear receptors, the high-affinity glucocorticoid receptor and the low-affinity pregnane X-receptor. We demonstrate that regulatory signals between these two nuclear receptors are necessary to optimize the body’s response to stress episodes, attenuating both the magnitude and duration of the biological response. In addition, we predict that the activation of pregnane X-receptor by multiple, low-affinity endobiotic ligands is necessary for the significant pregnane X-receptor-mediated transcriptional response observed following stress episodes. This integration allows responses mediated through both the high and low-affinity nuclear receptors, which we predict is an important strategy to minimize the risk of disease from chronic stress.
Luxembourg Centre for Systems Biomedicine (LCSB): Chemical Biology (Crawford Group)

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