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Received for publication April 11, 2005.
Revised August 10, 2005.
Accepted for publication August 10, 2005.
The constitutive androstane receptor, CAR, mediates the hepatic induction of various xenobiotic metabolizing enzymes and transporters following specific chemical exposures. Recent reports have established the existence of several human CAR mRNA splice variants, including a prominently expressed form termed CAR3, a receptor that possesses a 5 amino acid insertion within its ligand binding domain. Here we demonstrate that, in contrast to the constitutively active reference form of the receptor, CAR3 is ligand-activated, transactivating an optimized DR-4X3 reporter in response to the hCAR ligand, CITCO. The transactivation response requires the DBD and AF-2 motif of CAR3, and is markedly enhanced by RXR cotransfection. The stimulatory effects of RXR involve a unique mechanism as they were completely dependent on the RXR AF-2 function but independent of both the RXR A/B domain and its C domain/ heterodimerization region. Mammalian 2-hybrid results demonstrated that RXR enhanced CITCO-dependent interaction of CAR3 with the receptor interaction domain of SRC-1, indicating that RXR augments CAR3 activity by facilitating coactivator recruitment. Notably, clotrimazole also functions as a ligand activator of CAR3, in contrast to the inverse agonist activity exhibited by this agent on the reference form of the receptor. Further, results of transfection assays reveal that CAR3 is capable of transactivating the natural CYP2B6 and CYP3A4 gene enhancers, exhibiting both ligand- and RXR-dependence. These results demonstrate that unlike CAR1, CAR3 is a ligand activated receptor and that CAR3 may regulate gene expression in vivo in a manner distinct from the reference form of the receptor.
Key words:
DNA binding sites, Regulation - transcriptional, Regulation - xenobiotic, Toxicant-induced gene express
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