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CAR2 displays unique ligand binding and RXR heterodimerization characteristics Joshua G. DeKeyser, Scott S. Auerbach, Matthew A. Stoner and Curtis J. Omiecinski
 

Summary: CAR2 displays unique ligand binding and RXR heterodimerization characteristics
Joshua G. DeKeyser, Scott S. Auerbach, Matthew A. Stoner and Curtis J. Omiecinski
The constitutive androstane receptor (CAR, NR1I3) regulates the expression of
genes involved in all phases of xenobiotic metabolism. Alternative splicing of the
human CAR transcript yields an array of unique mRNAs. One form, termed CAR2,
contains an additional 4 amino acids (SPTV) that are predicted to reshape the
ligand-binding pocket. Results from the current studies demonstrate a marked,
ligand-independent, CAR2-mediated transactivation of reporters derived from the
natural CYP2B6 and CYP3A4 gene promoters. Over expression of RXR is
critical for achieving these effects. CAR2 interaction with SRC-1, assessed by
mammalian 2-hybrid experiments, is similarly dependent on RXR. Mutagenesis
of S233 (SPTV) to an alanine residue yielded a receptor possessing higher
constitutive activity. Alternatively, mutating S233 to an aspartate residue
drastically reduced CAR2's transactivation capacity, a result that correlates to their
ability to interact with RXR, and to recruit SRC-1 in an inverse-agonist regulated
manner. Together, these results demonstrate a robust RXR-dependent
recruitment of coactivators and transactivation by CAR2. In addition, CAR2's novel
dose response to clotrimazole and androstanol relative to the reference form of the
receptor suggests that CAR2 may be regulated by a unique set of ligands.
RESULTS

  

Source: Andrews, Anne M. - Huck Institutes of the Life Sciences, Pennsylvania State University

 

Collections: Biology and Medicine