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


CONCLUSIONS
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.
Lundell
Kerstin
K
The Atherosclerosis Research Unit, King Gustaf V Research Institute, Department of Medicine, Karolinska Institutet, Stockholm, Sweden. Kerstin.Lundell@ki.se
Thulin
Petra
P
Hamsten
Anders
A
Ehrenborg
Ewa
E
D020121:5' Untranslated Regions; D017398:Alternative Splicing; D002460:Cell Line; D045744:Cell Line, Tumor; D002896:Chromosomes, Human, Pair 6; D019295:Computational Biology / Q000379:methods; D018076:DNA, Complementary; D005091:Exons; D020224:Expressed Sequence Tags; D017930:Genes, Reporter; D014644:Genetic Variation; D023281:Genomics / Q000379:methods; D006367:HeLa Cells; D006801:Humans; D008156:Luciferases / Q000378:metabolism; D018482:Muscle, Skeletal / Q000166:cytology; D047494:PPAR delta / Q000096:biosynthesis* / Q000235:genetics*; D014176:Protein Biosynthesis; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D024363:Transcription Initiation Site; D015533:Transcriptional Activation
D020121:5' Untranslated Regions; D018076:DNA, Complementary; D047494:PPAR delta; D020033:Protein Isoforms; D012333:RNA, Messenger; D008156:Luciferases
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