Structural organization of mouse peroxisome proliferator-activated receptor gamma (mPPAR gamma) gene: alternative promoter use and different splicing yield two mPPAR gamma isoforms.

Abstract

To gain insight into the regulation of expression of peroxisome proliferator-activated receptor (PPAR) isoforms, we have determined the structural organization of the mouse PPAR 'y (mPPARy) gene. This gene extends > 105 kb and gives rise to two mRNAs (mPPARy1 and mPPARy2) that differ at their 5' ends. The mPPARy2 cDNA encodes an additional 30 amino acids N-terminal to the first ATG codon of mPPARyl and reveals a different 5' untranslated sequence.We show that mPPARy1 mRNA is encoded by eight exons, whereas the mPPARy2 mRNA is encoded by seven exons.Most of the 5' untranslated sequence of mPPARy1 mRNA is encoded by two exons, whereas the 5' untranslated sequence and the extra 30 N-terminal amino acids of mPPARy2 are encoded by one exon, which is located between the second and third exons coding for mPPARyl. The last six exons of mPPARy gene code for identical sequences in mPPARyl and mPPARy2 isoforms. The mPPARyl and mPPARy2 isoforms are transcribed from different promoters. The mPPARy gene has been mapped to chromosome 6 E3-F1 by in situ hybridization using a biotin-labeled probe. These results establish that at least one of the PPAR genes yields more than one protein product, similar to that encountered with retinoid X receptor and retinoic acid receptor genes. The existence of multiple PPAR isoforms transcribed from different promoters could increase the diversity of ligand and tissue-specific transcriptional responses.

Down regulation of peroxisome proliferator-activated receptorγ expression by inflammatory cytokines and its reversal by thiazolidinediones

“…The isoform PPARg is a relatively newly discovered member of the PPAR family that has been suggested to be involved in the regulation of not only adipocyte differentiation but also lipid metabolism and insulin action. Recent studies showed that the insulin-sensitizing thiazolidinedione class of compounds are synthetic ligands for PPARg and there seems to be a close relation between the potency of various thiazolidinediones to stimulate PPARg and their anti-diabetic action [22]. Although a large number of experimental rat models of obesity and insulin resistance have been used to study the pathogenesis, therapy and prevention of diabetes [23], molecular cloning of PPARg1 and g2 cDNAs have been reported only in mice and humans [13,20].…”

Novel Peroxisome Proliferator-activated Receptor (PPAR) γ and PPARδ Ligands Produce Distinct Biological Effects

“…Two closely related isoforms (PPAR␥1 and PPAR␥2), which differ by the addition of 30 NH 2 -terminal amino acids in PPAR␥2, occur as a result of alternative promoter usage and mRNA splicing (11,13). At the present time, no physiologically relevant differences in the function of these two isoforms have been determined (14).…”

Evolutionary conservation and adaptation in the mechanism that regulates SREBP action: what a long, strange tRIP it's been

“…Alternative promoter usage and differential splicing have been observed for many transcription factor genes, and in several instances this alters the structure of an activation domain. Most similar to SREBP-1, alternative promoters that result in N-terminal heterogeneity are common in the nuclear receptor family where different versions of an N-terminal constitutive activation domain (AF1) are produced (Zhu et al 1995;Oberste-Berghaus et al 2000;Huber et al 2002). However, in most cases, the real physiological significance of these variants has not been fully explored because most studies have focused on the nuclear receptor AF2 activation domain, which is located close to the ligand-binding domain at the C terminus.…”