Regulation and binding of pregnane X receptor by nuclear receptor corepressor silencing mediator of retinoid and thyroid hormone receptors (SMRT)

摘要: The pregnane X receptor (PXR) is an orphan nuclear predominantly expressed in liver and intestine. PXR coordinates hepatic responses to prevent injury induced by environmental toxins. activates cytochrome P450 3A4 gene expression upon binding rifampicin (Rif) clotrimazole (CTZ) recruiting transcriptional coactivators. It remains unclear whether how regulates the absence of ligand. In this study, we analyzed interactions between silencing mediator retinoid thyroid hormone receptors (SMRT) determined role SMRT regulating activity. We show that interacts with glutathione S-transferase pull-down, yeast two-hybrid, mammalian two-hybrid assays. interaction mediated through ligand-binding domain SMRTs' receptor-interacting 2. PXR-SMRT sensitive species-specific ligands, Rif causes exchange corepressor p160 coactivator known as receptor-associated 3 (RAC3). Deletion PXR's activation function 2 helix enhances abolishes ligand-dependent dissociation SMRT. Coexpression results colocalization at discrete foci. Finally, transient transfection assays overexpression inhibits transactivation Cyp3A4 promoter, whereas reporter expression. Taken together, our suggest may bind regulate activity PXR.