Preferential physical and functional interaction of pregnane X receptor with the SMRTalpha isoform.-猫眼课题宝

DOI：

10.1124/mol.108.047845

发表时间：

2009-02

期刊：

MOLECULAR PHARMACOLOGY

影响因子：

3.6

通讯作者：

中科院分区：

医学3区

文献类型：

作者：

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

来源链接：

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2629818/?report=classic

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 contains only an extra 46-amino acid sequence inserted immediately downstream from the C-terminal corepressor motif. Currently 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 SMRTτ both in vitro and in vivo. Interestingly, the PXR-SMRTα interaction is also resistant to PXR ligand-induced dissociation, in contrast to the PXR-SMRTτ interaction. Consistently, SMRTα inhibits PXR activity more efficiently than does SMRTτ in transfection assays, while 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. Specifically, 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 Tyr 2354 and Asp 2355 residues of the SMRTα insert are most critical for the enhanced interaction. Additionally, expression data show that SMRTα is more abundantly expressed in most human tissues and caner cell lines, and together these data suggest that SMRTα may play a more important role than SMRTτ in the negative regulation of PXR.