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

ABSTRACT: BACKGROUND: Peroxisome proliferator-activated receptor delta (PPAR delta) is a member of the nuclear receptor superfamily. Numerous studies have aimed at unravelling the physiological role of PPAR delta as a transcriptional regulator whereas the regulation of PPAR delta gene expression has been less studied. RESULTS: The principal transcription start site in the human PPAR delta 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 PPAR delta mRNA, with an impact on translation efficiency, suggests a translational regulation of human PPAR delta expression. Five untranslated exons identified in this study contribute to the variability among the 5'-UTRs of human PPAR delta mRNAs. Moreover, in vitro studies of a 3'-splice transcript encoding a truncated variant of PPAR delta (designated PPAR delta 2) show that this isoform constitutes a potential dominant negative form of the receptor. CONCLUSION: We propose that alternative splicing of human PPAR delta constitutes an intrinsic role for the regulation of PPAR delta expression and thus activity, and highlight the significance of alternative splicing of this nuclear receptor in physiology and disease.

SUBMITTER: Lundell K

PROVIDER: S-EPMC2045109 | biostudies-literature | 2007

REPOSITORIES: biostudies-literature

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

Lundell Kerstin K Thulin Petra P Hamsten Anders A Ehrenborg Ewa E

BMC molecular biology 20070816

<h4>Background</h4>Peroxisome proliferator-activated receptor delta (PPAR delta) is a member of the nuclear receptor superfamily. Numerous studies have aimed at unravelling the physiological role of PPAR delta as a transcriptional regulator whereas the regulation of PPAR delta gene expression has been less studied.<h4>Results</h4>The principal transcription start site in the human PPAR delta gene identified here is positioned upstream of exon 1, although four alternative 5'-ends related to downs ...[more]

PMID: 17705821

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Project description:Although MK886 was originally identified as an inhibitor of 5-lipoxygenase activating protein (FLAP), recent data demonstrate that this activity does not underlie its ability to induce apoptosis [Datta, Biswal and Kehrer (1999) Biochem. J. 340, 371--375]. Since FLAP is a fatty-acid binding protein, it is conceivable that MK886 may affect other such proteins. A family of nuclear receptors that are activated by fatty acids and their metabolites, the peroxisome-proliferator-activated receptors (PPARs), have been implicated in apoptosis and may represent a target for MK886. The ability of MK886 to inhibit PPAR-alpha, -beta and -gamma activity was assessed using reporter assay systems (peroxisome-proliferator response element--luciferase). Using a transient transfection system in monkey kidney fibroblast CV-1 cells, mouse keratinocyte 308 cells and human lung adenocarcinoma A549 cells, 10--20 microM MK886 inhibited Wy14,643 activation of PPAR alpha by approximately 80%. Similar inhibition of PPAR alpha by MK886 was observed with a stable transfection reporter system in CV-1 cells. Only minimal inhibitory effects were seen on PPAR beta and PPAR gamma. MK886 inhibited PPAR alpha by a non-competitive mechanism as shown by its effects on the binding of arachidonic acid to PPAR alpha protein, and a dose-response study using a transient transfection reporter assay in COS-1 cells. An assay assessing PPAR ligand-receptor interactions showed that MK886 prevents the conformational change necessary for active-complex formation. The expression of keratin-1, a protein encoded by a PPAR alpha-responsive gene, was reduced by MK886 in a culture of mouse primary keratinocytes, suggesting that PPAR inhibition has functional consequences in normal cells. Although Jurkat cells express all PPAR isoforms, various PPAR alpha and PPAR gamma agonists were unable to prevent MK886-induced apoptosis. This is consistent with MK886 functioning as a non-competitive inhibitor of PPAR alpha, but may also indicate that PPAR alpha is not directly involved in MK886-induced apoptosis. Although numerous PPAR activators have been identified, the results show that MK886 can inhibit PPAR alpha, making it the first compound identified to have such an effect.

Dataset Information

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

Publications

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

Similar Datasets

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