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Research ArticleArticle

CAR2 Displays Unique Ligand Binding and RXRα Heterodimerization Characteristics

Scott S. Auerbach, Joshua G. DeKeyser, Matthew A. Stoner and Curtis J. Omiecinski
Drug Metabolism and Disposition March 2007, 35 (3) 428-439; DOI: https://doi.org/10.1124/dmd.106.012641
Scott S. Auerbach
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Joshua G. DeKeyser
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Matthew A. Stoner
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Curtis J. Omiecinski
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Abstract

The constitutive androstane receptor (CAR; NR1I3) regulates the expression of genes involved in xenobiotic metabolism. Alternative splicing of the human CAR gene yields an array of mRNAs that encode structurally diverse proteins. One form of CAR, termed CAR2, contains an additional four amino acids (SPTV) that are predicted to reshape the ligand-binding pocket. The current studies show a marked, ligand-independent, CAR2-mediated transactivation of reporters containing optimal DR-3, DR-4, and DR-5 response elements, and reporters derived from the natural CYP2B6 and CYP3A4 gene promoters. Overexpression of the RXRα ligand binding domain was critical for achieving these effects. CAR2 interaction with SRC-1 was similarly dependent on the coexpression of RXRα. Mutagenesis of Ser233 (SPTV) to an alanine residue yielded a receptor possessing higher constitutive activity. Alternatively, mutating Ser233 to an aspartate residue drastically reduced the transactivation capacity of CAR2. The respective abilities of these mutagenized forms of CAR2 to transactivate a DR-4 × 3 reporter element correlated with their ability to interact with RxRα and to recruit SRC-1 in a ligand-regulated manner. Together, these results demonstrate a robust RXRα-dependent recruitment of coactivators and transactivation by CAR2. In addition, CAR2 displays novel dose responses to clotrimazole and androstanol compared with the reference form of the receptor while at the same time retaining the ability to bind CITCO. This result supports a hypothesis whereby the four-amino-acid insertion in CAR2 structurally modifies its ligand binding pocket, suggesting that CAR2 is regulated by a set of ligands distinct from those governing the activity of reference CAR.

Footnotes

  • This work was supported by Grant GM66411 from the National Institute of General Medical Sciences (to C.J.O.) and National Institute of Environmental Health Sciences Training Grant ES07032 (to S.S.A.).

  • Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.

  • doi:10.1124/dmd.106.012641.

  • ABBREVIATIONS: NR, nuclear receptor; CAR, constitutive androstane receptor; RXR, retinoid X receptor; FXR, farnesoid X receptor; DBD, DNA-binding domain; LBD, ligand-binding domain; DR, direct repeat; PBREM, phenobarbital response enhancer module; XREM, xenobiotic response enhancer module; CMV, cytomegalovirus; VP16, virus protein 16; EMSA, electrophoretic mobility shift assay; CITCO, 6-(4-chlorophenyl: imidazo[2,1-b]thiazole-5-carbaldehyde O-(3,4-dichlorobenzyl)oxime; h, human; m, mouse; SRC-1, steroid receptor coactivator 1; bp, base pair(s); DMSO, dimethyl sulfoxide; AF-2, activation function 2; RID, receptor interaction domain.

    • Received August 30, 2006.
    • Accepted December 27, 2006.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 35 (3)
Drug Metabolism and Disposition
Vol. 35, Issue 3
1 Mar 2007
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Research ArticleArticle

CAR2 Displays Unique Ligand Binding and RXRα Heterodimerization Characteristics

Scott S. Auerbach, Joshua G. DeKeyser, Matthew A. Stoner and Curtis J. Omiecinski
Drug Metabolism and Disposition March 1, 2007, 35 (3) 428-439; DOI: https://doi.org/10.1124/dmd.106.012641

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Research ArticleArticle

CAR2 Displays Unique Ligand Binding and RXRα Heterodimerization Characteristics

Scott S. Auerbach, Joshua G. DeKeyser, Matthew A. Stoner and Curtis J. Omiecinski
Drug Metabolism and Disposition March 1, 2007, 35 (3) 428-439; DOI: https://doi.org/10.1124/dmd.106.012641
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