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The evolution of drug-activated nuclear receptors : one ancestral gene diverged into two xenosensor genes in mammals

Handschin, C. and Blattler, S. and Roth, A. and Looser, R. and Oscarson, M. and Kaufmann, M. R. and Podvinec, M. and Gnerre, C. and Meyer, U. A.. (2004) The evolution of drug-activated nuclear receptors : one ancestral gene diverged into two xenosensor genes in mammals. Nuclear Receptor, Vol. 2, H. 1. p. 7.

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Official URL: http://edoc.unibas.ch/dok/A5259308

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Abstract

BACKGROUND: Drugs and other xenobiotics alter gene expression of cytochromes P450 (CYP) by activating the pregnane X receptor (PXR) and constitutive androstane receptor (CAR) in mammals. In non-mammalian species, only one xenosensor gene has been found. Using chicken as a model organism, the aim of our study was to elucidate whether non-mammalian species only have one or two xenosensors like mammals. RESULTS: To explore the evolutionary aspect of this divergence, we tried to identify additional xenobiotic sensing nuclear receptors in chicken using various experimental approaches. However, none of those revealed novel candidates. Ablation of chicken xenobiotic receptor (CXR) function by RNAi or dominant-negative alleles drastically reduced drug-induction in a chicken hepatoma cell line. Subsequently, we functionally and structurally characterized CXR and compared our results to PXR and CAR. Despite the high similarity in their amino acid sequence, PXR and CAR have very distinct modes of activation. Some aspects of CXR function, e.g. direct ligand activation and high promiscuity are very reminiscent of PXR. On the other hand, cellular localization studies revealed common characteristics of CXR and CAR in terms of cytoplasmic-nuclear distribution. Finally, CXR has unique properties regarding its regulation in comparison to PXR and CAR. CONCLUSION: Our finding thus strongly suggest that CXR constitutes an ancestral gene which has evolved into PXR and CAR in mammals. Future studies should elucidate the reason for this divergence in mammalian versus non-mammalian species.
Faculties and Departments:05 Faculty of Science > Departement Biozentrum > Services Biozentrum > Research IT (Podvinec)
05 Faculty of Science > Departement Biozentrum > Growth & Development > Growth & Development (Handschin)
UniBasel Contributors:Handschin, Christoph and Podvinec, Michael
Item Type:Article, refereed
Article Subtype:Research Article
Bibsysno:Link to catalogue
Publisher:BioMed Central
ISSN:1478-1336
Note:Publication type according to Uni Basel Research Database: Journal article
Language:English
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Last Modified:31 Dec 2015 10:42
Deposited On:22 Mar 2012 13:22

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