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Preferential Physical and Functional Interaction of Pregnane X Receptor with the SMRT Isoform

Department of Pharmacology, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, Piscataway, New Jersey

The silencing mediator for retinoid and thyroid hormone receptors (SMRT) serves as a platform for transcriptional repression elicited by several steroid/nuclear receptors and transcription factors. SMRT exists in two major splicing isoforms, and , with SMRT containing only an extra 46-amino acid sequence inserted immediately downstream from the C-terminal corepressor motif. Little is known about potential functional differences between these two isoforms. Here we show that the pregnane X receptor (PXR) interacts more strongly with SMRT than with SMRT both in vitro and in vivo. It is interesting that the PXR-SMRT interaction is also resistant to PXR ligand-induced dissociation, in contrast to the PXR-SMRT interaction. SMRT consistently inhibits PXR activity more efficiently than does SMRT in transfection assays, although they possess comparable intrinsic repression activity and association with histone deacetylase. We further show that the mechanism for the enhanced PXR-SMRT interaction involves both the 46-amino acid insert and the C-terminal corepressor motif. In particular, the first five amino acids of the SMRT insert are essential and sufficient for the enhanced binding of SMRT to PXR. Furthermore, we demonstrate that Tyr2354 and Asp2355 residues of the SMRT insert are most critical for the enhanced interaction. In addition, expression data show that SMRT is more abundantly expressed in most human tissues and cancer cell lines, and together these data suggest that SMRT may play a more important role than SMRT in the negative regulation of PXR.

Received for publication April 10, 2008.

Accepted for publication October 30, 2008.

Address correspondence to: Dr. J. Don Chen, Department of Pharmacology, UMDNJ-Robert Wood Johnson Medical School, 661 Hoes Lane, Piscataway, NJ 08854-5635. E-mail: chenjd{at}umdnj.edu