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Received for publication March 31, 2005.
Revised October 8, 2005.
Accepted for publication October 11, 2005.
The pregnane X receptor (PXR) is an orphan nuclear receptor predominantly expressed in liver and intestine. PXR coordinates hepatic responses to prevent liver injury induced by environmental toxins. PXR activates cytochrome P450 (CYP) 3A4 gene expression upon binding to rifampicin (Rif) and clotrimazole (CTZ) by recruiting transcriptional coactivators. Whether and how PXR regulates gene expression in the absence of ligand remains unclear. Here we analyzed interactions between PXR and the nuclear receptor corepressor SMRT (silencing mediator of retinoid and thyroid hormone receptors) and determined the role of SMRT in regulating PXR activity. We show that SMRT interacts with PXR in GST pull down, yeast two-hybrid and mammalian two-hybrid assays. The interaction is mediated through the ligand-binding domain of PXR and the SMRT ID2 domain. The PXR-SMRT interaction is sensitive to species-specific ligands, and Rif causes an exchange of the corepressor SMRT with the p160 coactivator RAC3. Deletion of the PXR's AF2 helix enhances SMRT binding, and abolishes ligand-dependent dissociation of SMRT. Coexpression of PXR with SMRT results in colocalization at discrete nuclear foci. Finally, transient transfection assays show that SMRT may inhibit PXR's transactivation of the CYP3A4 gene, and that silencing of SMRT by siRNA may enhance Cyp3A4 expression. Taken together, our results suggest that the corepressor SMRT may bind to and regulate the transcriptional activity of PXR.
Key words:
PPARs, Transcriptional coactivators, Cytochrome P450, Regulation - transcriptional, Regulation - xenobiotic, Structure/function/mechanism
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