title: Expression level and agonist-binding affect the turnover, ubiquitination and complex formation of peroxisome proliferator activated receptor beta.
abstract: 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 PPARbeta subtype (also known as PPARdelta). Our data show that the ubiquitination and degradation of PPARbeta is not significantly influenced by the synthetic agonist GW501516 under conditions of moderate PPARbeta expression. By contrast, the overexpression of PPARbeta dramatically enhanced its degradation concomitant with its polyubiquitination and the formation of high molecular mass complexes containing multiple, presumably oligomerized PPARbeta molecules that lacked stoichiometical amounts of the obligatory PPARbeta dimerization partner, retinoid X receptor. The formation of these apparently aberrant complexes, as well as the ubiquitination and destabilization of PPARbeta, were strongly inhibited by GW501516. Our findings suggest that PPARbeta is subject to complex post-translational regulatory mechanisms that partly may serve to safeguard the cell against deregulated PPARbeta expression. Furthermore, our data have important implications regarding the widespread use of overexpression systems to evaluate the function and regulation of PPARs.
authors.affiliation: Institute of Molecular Biology and Tumor Research, Philipps University, Marburg, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Rieck
authors.forename: Lena
authors.initials: L
authors.lastname: Wedeken
authors.forename: Sabine
authors.initials: S
authors.lastname: Müller-Brüsselbach
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Meissner
authors.forename: Rolf
authors.initials: R
authors.lastname: Müller
mesh_terms: D000818:Animals; D002460:Cell Line; D002850:Chromatography, Gel; D006801:Humans; D047468:Immunoprecipitation; D008024:Ligands; D051379:Mice; D048068:PPAR-beta / Q000819:agonists / Q000378:metabolism*; D013844:Thiazoles / Q000494:pharmacology; D025801:Ubiquitin / Q000378:metabolism*