ArticleNuclear receptor2004
Alternative splicing affects the function and tissue-specific expression of the human constitutive androstane receptor.
Article in Nuclear receptor, 2004. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 39 papers.
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Who cites it
39 citing papers in PubMed, 85 citations in OpenAlex.
- Isoform-level expression of the constitutive androstane receptor (CAR or NR1I3) transcription factor better predicts the mRNA expression of the cytochrome P450s in human liver samples.Drug metabolism and disposition: the biological fate of chemicals · 2025Article
- Constitutive Androstane Receptor Regulates Germ Cell Homeostasis, Sperm Quality, and Male Fertility via Akt-Foxo1 Pathway.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2024Article
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- Article
- Review
- The Endocrine Function of Osteocalcin Regulated by Bone Resorption: A Lesson from Reduced and Increased Bone Mass Diseases.International journal of molecular sciences · 2019Review
- Osteocalcin‑GPRC6A: An update of its clinical and biological multi‑organic interactions (Review).Molecular medicine reports · 2019Review
- Allosteric pathways in nuclear receptors - Potential targets for drug design.Pharmacology & therapeutics · 2018Review
- RNA Sequencing Reveals Age and Species Differences of Constitutive Androstane Receptor-Targeted Drug-Processing Genes in the Liver.Drug metabolism and disposition: the biological fate of chemicals · 2017Article
- Constitutive androstane receptor regulates the intestinal mucosal response to injury.British journal of pharmacology · 2017Article
- Mechanisms of xenobiotic receptor activation: Direct vs. indirect.Biochimica et biophysica acta · 2016Review
- Nuclear receptors and nonalcoholic fatty liver disease.Biochimica et biophysica acta · 2016Review
- Small-molecule modulators of PXR and CAR.Biochimica et biophysica acta · 2016Review
- Nonsterol Isoprenoids Activate Human Constitutive Androstane Receptor in an Isoform-Selective Manner in Primary Cultured Mouse Hepatocytes.Drug metabolism and disposition: the biological fate of chemicals · 2016Article
- Small-molecule modulators of the constitutive androstane receptor.Expert opinion on drug metabolism & toxicology · 2015Review
- Differential activation of human constitutive androstane receptor and its SV23 and SV24 splice variants by rilpivirine and etravirine.British journal of pharmacology · 2015Article
- Carboxymefloquine, the major metabolite of the antimalarial drug mefloquine, induces drug-metabolizing enzyme and transporter expression by activation of pregnane X receptor.Antimicrobial agents and chemotherapy · 2015Article
- Structural and functional similarity of amphibian constitutive androstane receptor with mammalian pregnane X receptor.PloS one · 2014Article
- Indirect activation of the SV23 and SV24 splice variants of human constitutive androstane receptor: analysis with 3-hydroxyflavone and its analogues.British journal of pharmacology · 2013Article
- Xenobiotic-sensing nuclear receptors involved in drug metabolism: a structural perspective.Drug metabolism reviews · 2013Review
Corrections and comments
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundThe constitutive androstane receptor (CAR) plays a key role in the control of drug metabolism and transport by mediating the phenobarbital-type induction of many phase I and II drug metabolizing enzymes and drug transporters.
resultsWe identified transcripts generated by four different alternative splicing events in the human CAR gene. Two of the corresponding ligand binding domain isoforms demonstrated novel functional properties: First, CAR(SV3), which is encoded by a transcript containing an lengthened exon 7, differentially transactivated target gene promoters. Second, CAR(SV2), which results from the use of an alternative 3' splice site lengthening exon 8, showed ligand-dependent instead of constitutive interaction with coactivators. Furthermore, alternatively spliced transcripts demonstrated a tissue-specific expression pattern. In most tissues, only transcripts generated by alternative splicing within exon 9 were expressed. The encoded variant demonstrated a loss-of-function phenotype. Correct splicing of exon 8 to exon 9 is restricted to only a few tissues, among them liver and small intestine for which CAR function has been demonstrated, and is associated with the induction of CAR expression during differentiation of intestinal cells.
conclusionDue to their specific activities, CAR variant proteins SV2 and SV3 may modulate the activity of reference CAR(SV1). Furthermore, we propose that transcriptional activation and regulation of splicing of exon 9 may be coupled to ensure appropriate tissue- and differentiation state-specific expression of transcripts encoding functional CAR protein. Altogether, alternative splicing seems to be of utmost importance for the regulation of CAR expression and function.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.