| Expression of Human CAR Splicing Variants in BAC-Transgenic Mice. | |
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MedLine Citation:
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PMID: 23152187 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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The nuclear receptor constitutive androstane receptor (CAR) is a key regulator for drug metabolism in liver. Human CAR (hCAR) transcripts are subjected to alternative splicing. Some hCAR splicing variants (SVs) have been shown to encode functional proteins by reporter assays. However, in vivo research on the activity of these hCAR SVs has been impeded by the absence of a valid model. The current study engineered an hCAR-BAC-transgenic (hCAR-TG) mouse model by integrating the 8.5-kb hCAR gene as well as 73-kb upstream and 91-kb downstream human genomic DNA into the genome of CAR-null mice. A series of experiments demonstrate that (1) the expression of major hCAR mRNA SVs, SV0-4, in livers of hCAR-TG mice is comparable to that in human livers; (2) the hCAR SVs are predominantly expressed in liver, which resembles the tissue distribution of CAR in humans, but diverges from that in mice; (3) major hCAR mRNA SVs increase markedly in postnatal livers of hCAR-TG mice, which mimics the ontogeny of CAR mRNA in humans. Thus, the transgene likely contains all the functional regulatory elements controlling proper spatial and temporal expression of the hCAR gene. Moreover, hCAR-TG mice respond to the hCAR-specific agonist CITCO instead of the mouse CAR agonist TCPOBOP, as well as the common CAR activator, phenobarbital, suggesting that hCAR is fully functional in livers of transgenic mice. In summary, the hCAR-TG mice developed by the current study represent a valid model for studying in vivo function and regulation of hCAR and its splicing variants. |
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Authors:
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Yu-Kun Jennifer Zhang; Hong Lu; Curtis Klaassen |
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Publication Detail:
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Type: JOURNAL ARTICLE Date: 2012-11-14 |
Journal Detail:
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Title: Toxicological sciences : an official journal of the Society of Toxicology Volume: - ISSN: 1096-0929 ISO Abbreviation: Toxicol. Sci. Publication Date: 2012 Nov |
Date Detail:
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Created Date: 2012-11-15 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 9805461 Medline TA: Toxicol Sci Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Affiliation:
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Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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