Preferential physical and functional interaction of pregnane X receptor with the SMRTα isoform

Chia Wei Li, Gia Khanh Dinh, J. Don Chen

Research output: Contribution to journalArticlepeer-review

10 Scopus citations

Abstract

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, α and τ, with SMRTα containing only an extra 46-amino acid sequence inserted immediately downstream from the C-terminal core- pressor 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 SMRTα than with SMRTτboth in vitro and in vivo. It is interesting that the PXR-SMRTα interaction is also resistant to PXR ligand- induced dissociation, in contrast to the PXR-SMRTτ interaction. SMRTα consistently inhibits PXR activity more efficiently than does SMRTτ 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-SMRTα interaction involves both the 46-amino acid insert and the C-terminal corepressor motif. In particular, the first five amino acids of the SMRTα insert are essential and sufficient for the enhanced binding of SMRTα to PXR. Furthermore, we demonstrate that Tyr2354 and Asp2355 residues of the SMRTa insert are most critical for the enhanced interaction. In addition, expression data show that SMRTα is more abundantly expressed in most human tissues and cancer cell lines, and together these data suggest that SMRTα may play a more important role than SMRTτ in the negative regulation of PXR.

Original languageEnglish (US)
Pages (from-to)363-373
Number of pages11
JournalMolecular pharmacology
Volume75
Issue number2
DOIs
StatePublished - Feb 2009

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Pharmacology

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