title: Optimization of stress response through the nuclear receptor-mediated cortisol signalling network.
abstract: 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.
authors: Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Campus Belval, L-4362 Esch-sur-Alzette, Luxembourg.
authors: Alexey
authors: A
authors: Kolodkin
authors: Nilgun
authors: N
authors: Sahin
authors: Anna
authors: A
authors: Phillips
authors: Steve R
authors: SR
authors: Hood
authors: Frank J
authors: FJ
authors: Bruggeman
authors: Hans V
authors: HV
authors: Westerhoff
authors: Nick
authors: N
authors: Plant
mesh_terms: D000222:Adaptation, Physiological; D025461:Feedback, Physiological; D053263:Gene Regulatory Networks; D006801:Humans; D006854:Hydrocortisone / Q000378:metabolism*; D008024:Ligands; D008954:Models, Biological; D000077297:Pregnane X Receptor; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D011965:Receptors, Glucocorticoid / Q000378:metabolism; D011987:Receptors, Steroid / Q000378:metabolism; D015203:Reproducibility of Results; D015398:Signal Transduction / Q000235:genetics; D013312:Stress, Physiological / Q000235:genetics
chemical_list: D008024:Ligands; D000077297:Pregnane X Receptor; D018160:Receptors, Cytoplasmic and Nuclear; D011965:Receptors, Glucocorticoid; D011987:Receptors, Steroid; D006854:Hydrocortisone
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