Expression level and agonist-binding affect the turnover, ubiquitination and complex formation of peroxisome proliferator activated receptor β

Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear hormone receptor superfamily that modulate target gene expression in response to fatty acid ligands. Their regulation by post-translational modifications has been reported but is poorly understood. In the present study, w...

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Bibliographic Details
Published in:The FEBS journal 2007-10, Vol.274 (19), p.5068-5076
Main Authors: Rieck, Markus, Wedeken, Lena, Müller-Brüsselbach, Sabine, Meissner, Wolfgang, Müller, Rolf
Format: Article
Language:English
Subjects:
Animals
Cell Line
Chromatography, Gel
GW501516
Humans
Immunoprecipitation
Ligands
Mice
polyubiquitination
PPAR-beta - agonists
PPAR-beta - metabolism
PPARβ
Thiazoles - pharmacology
ubiquitin
Ubiquitin - metabolism
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Summary:Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear hormone receptor superfamily that modulate target gene expression in response to fatty acid ligands. Their regulation by post-translational modifications has been reported but is poorly understood. In the present study, we investigated whether ligand binding affects the turnover and ubiquitination of the PPARβ subtype (also known as PPARδ). Our data show that the ubiquitination and degradation of PPARβ is not significantly influenced by the synthetic agonist GW501516 under conditions of moderate PPARβ expression. By contrast, the overexpression of PPARβ dramatically enhanced its degradation concomitant with its polyubiquitination and the formation of high molecular mass complexes containing multiple, presumably oligomerized PPARβ molecules that lacked stoichiometical amounts of the obligatory PPARβ dimerization partner, retinoid X receptor. The formation of these apparently aberrant complexes, as well as the ubiquitination and destabilization of PPARβ, were strongly inhibited by GW501516. Our findings suggest that PPARβ is subject to complex post-translational regulatory mechanisms that partly may serve to safeguard the cell against deregulated PPARβ expression. Furthermore, our data have important implications regarding the widespread use of overexpression systems to evaluate the function and regulation of PPARs.
ISSN:1742-464X
1742-4658
DOI:10.1111/j.1742-4658.2007.06037.x