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Optimization of stress response through the nuclear receptor-mediated cortisol signalling network

Kolodkin, A, Sahin, N, Phillips, A, Hood, SR, Bruggeman, FJ, Westerhoff, HV and Plant, NJ (2013) Optimization of stress response through the nuclear receptor-mediated cortisol signalling network Nature Communications, 4, 1792.

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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 (GR) and the low affinity pregnane X-receptor (PXR). We demonstrate that regulatory signals between these two nuclear receptors are necessary to optimise 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 PXR by multiple, low affinity endobiotic ligands is necessary for the significant PXR-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 minimise the risk of disease from chronic stress.

Item Type: Article
Divisions : Faculty of Health and Medical Sciences > School of Biosciences and Medicine > Department of Biochemical Sciences
Authors :
AuthorsEmailORCID
Kolodkin, AUNSPECIFIEDUNSPECIFIED
Sahin, NUNSPECIFIEDUNSPECIFIED
Phillips, AUNSPECIFIEDUNSPECIFIED
Hood, SRUNSPECIFIEDUNSPECIFIED
Bruggeman, FJUNSPECIFIEDUNSPECIFIED
Westerhoff, HVUNSPECIFIEDUNSPECIFIED
Plant, NJUNSPECIFIEDUNSPECIFIED
Date : 30 April 2013
Identification Number : 10.1038/ncomms2799
Uncontrolled Keywords : Computational Biology, Stress, Nuclear receptor, PXR, GR
Related URLs :
Additional Information : This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported License.
Depositing User : Symplectic Elements
Date Deposited : 14 May 2013 17:49
Last Modified : 23 Sep 2013 20:07
URI: http://epubs.surrey.ac.uk/id/eprint/771370

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