Evolutionary History and Functional Characterization of the Amphibian Xenosensor CAR

The xenosensing constitutive androstane receptor (CAR) is widely considered to have arisen in early mammals via duplication of the pregnane X receptor (PXR). We report that CAR emerged together with PXR and the vitamin D receptor from an ancestral NR1I gene already in early vertebrates, as a result...

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Published in:Molecular endocrinology (Baltimore, Md.) Md.), 2012-01, Vol.26 (1), p.14-26
Main Authors: Mathäs, Marianne, Burk, Oliver, Qiu, Huan, Nußhag, Christian, Gödtel-Armbrust, Ute, Baranyai, Dorothea, Deng, Shiwei, Römer, Kristin, Nem, Dieudonné, Windshügel, Björn, Wojnowski, Leszek
Format: Article
Language:English
Subjects:
Amino Acid Sequence
Amniota
Animals
Biological Evolution
Cell Line
Evolution, Molecular
Gene Expression Regulation
Humans
Molecular Sequence Data
Oligonucleotide Array Sequence Analysis
Original Research
Phylogeny
Receptors, Calcitriol - genetics
Receptors, Calcitriol - metabolism
Receptors, Cytoplasmic and Nuclear - genetics
Receptors, Cytoplasmic and Nuclear - metabolism
Receptors, Steroid - genetics
Receptors, Steroid - metabolism
RNA, Messenger - genetics
Sequence Alignment
Xenopus
Xenopus - genetics
Xenopus - metabolism
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Summary:The xenosensing constitutive androstane receptor (CAR) is widely considered to have arisen in early mammals via duplication of the pregnane X receptor (PXR). We report that CAR emerged together with PXR and the vitamin D receptor from an ancestral NR1I gene already in early vertebrates, as a result of whole-genome duplications. CAR genes were subsequently lost from the fish lineage, but they are conserved in all taxa of land vertebrates. This contrasts with PXR, which is found in most fish species, whereas it is lost from Sauropsida (reptiles and birds) and plays a role unrelated to xenosensing in Xenopus. This role is fulfilled in Xenopus by CAR, which exhibits low basal activity and pronounced responsiveness to activators such as drugs and steroids, altogether resembling mammalian PXR. The constitutive activity typical for mammalian CAR emerged first in Sauropsida, and it is thus common to all fully terrestrial land vertebrates (Amniota). The constitutive activity can be achieved by humanizing just two amino acids of the Xenopus CAR. Taken together, our results provide a comprehensive reconstruction of the evolutionary history of the NR1I subfamily of nuclear receptors. They identify CAR as the more conserved and remarkably plastic NR1I xenosensor in land vertebrates. Nonmammalian CAR should help to dissect the specific functions of PXR and CAR in the metabolism of xeno- and endobiotics in humans. Xenopus CAR is a first reported amphibian xenosensor, which opens the way to toxicogenomic and bioaugmentation studies in this critically endangered taxon of land vertebrates.
ISSN:0888-8809
1944-9917
DOI:10.1210/me.2011-1235