Alternative splicing of human peroxisome proliferator-activated receptor delta (PPARdelta):effects on translation efficiency and trans-activation ability

Kerstin Lundell,Ewa Ehrenborg,Petra Thulin,Anders Hamsten

doi:10.1186/1471-2199-8-70

Abstract

BackgroundPeroxisome proliferator-activated receptor delta (PPARδ) is a member of the nuclear receptor superfamily. Numerous studies have aimed at unravelling the physiological role of PPARδ as a transcriptional regulator whereas the regulation of PPARδ gene expression has been less studied.ResultsThe principal transcription start site in the human PPARδ gene identified here is positioned upstream of exon 1, although four alternative 5'-ends related to downstream exons were identified. The demonstration of multiple 5'-UTR splice variants of PPARδ mRNA, with an impact on translation efficiency, suggests a translational regulation of human PPARδ expression. Five untranslated exons identified in this study contribute to the variability among the 5'-UTRs of human PPARδ mRNAs. Moreover, in vitro studies of a 3'-splice transcript encoding a truncated variant of PPARδ (designated PPARδ2) show that this isoform constitutes a potential dominant negative form of the receptor.ConclusionWe propose that alternative splicing of human PPARδ constitutes an intrinsic role for the regulation of PPARδ expression and thus activity, and highlight the significance of alternative splicing of this nuclear receptor in physiology and disease.

Highlights

Peroxisome proliferator-activated receptor delta (PPARδ) is a member of the nuclear receptor superfamily
Ligand activation of peroxisome proliferator-activated receptor (PPAR) induces conformational changes that promote binding of co-activators that are essential for the trans-activating function whereas binding of nuclear corepressors is associated with transcriptional repression
The open reading frame (ORF) region encoded by exons 4 to 9 remains identical in all 5'-spliced transcripts

Summary

Introduction

Peroxisome proliferator-activated receptor delta (PPARδ) is a member of the nuclear receptor superfamily. Peroxisome proliferator-activated receptors (PPARs) are ligand-dependent transcription factors that activate target genes by binding to peroxisome proliferator response elements (PPREs) as heterodimers with the retinoid × receptor (RXR) (NR2B). Three PPAR isoforms encoded by different genes have been identified: α (PPARα or NR1C1), δ/β (PPARδ or NR1C2) and γ (PPARγ or NR1C3). The functional specificity among members of the PPAR subfamily is achieved by isoform-specific tissue expression as well as ligand binding specificity [1,2,3,4,5]. Ligand activation of PPARs induces conformational changes that promote binding of co-activators that are essential for the trans-activating function whereas binding of nuclear corepressors is associated with transcriptional repression. PPARδ is the only isoform that maintains repressor activity when bound to DNA. It has been reported that unligated PPARδ can act as an intrinsic transcription repressor (page number not for citation purposes)

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