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.
Kolodkin et al_NatComms.pdf
Available under License : See the attached licence file.
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.
|Divisions :||Faculty of Health and Medical Sciences > School of Biosciences and Medicine > Department of Biochemical Sciences|
|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|
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