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J. Biol. Chem., Vol. 281, Issue 32, 22597-22604, August 11, 2006

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Peroxisome Proliferator-activated Receptor-1 Is Dephosphorylated and Degraded during BAY 11-7085-induced Synovial Fibroblast Apoptosis^*

Biserka Relic, Valérie Benoit, Nathalie Franchimont, Marie-Joelle Kaiser, Jean-Philippe Hauzeur, Philippe Gillet^¶, Marie-Paule Merville, Vincent Bours, and Michel G. Malaise¹

From the Center for Biomedical Integrative Genoproteomics (CBIG), Department of Rheumatology, Department of Medical Chemistry and Human Genetics and ^¶Department of Orthopedic Surgery, University of Liège, 4000 Liège, Belgium

Peroxisome proliferator-activated receptor- (PPAR-) plays a central role in whole body metabolism by regulating adipocyte differentiation and energy storage. Recently, however, PPAR- has also been demonstrated to affect proliferation, differentiation, and apoptosis of different cell types. As we have previously shown that BAY 11-7085-induced synovial fibroblast apoptosis is prevented by PPAR- agonist 15d-PGJ2; the expression of PPAR- in these cells was studied. Both PPAR-1 and PPAR-2 isoforms were cloned from synovial fibroblast RNA, but only PPAR-1 was detected by Western blot, showing constitutive nuclear expression. Within minutes of BAY 11-7085 treatment, a PPAR-1-specific band was shifted into a form of higher mobility, suggesting dephosphorylation, as confirmed by phosphatase treatment of cell extracts. Of interest, BAY 11-7085-induced PPAR-1 dephosphorylation was followed by PARP and caspase-8 cleavage as well as by PPAR-1 protein degradation. PPAR-1 dephosphorylation was followed by the loss of PPAR-DNA binding activity ubiquitously present in synovial fibroblast nuclear extracts. Unlike the phosphorylated form, dephosphorylated PPAR-1 was found in insoluble membrane cell fraction and was not ubiquitinated before degradation. PPAR-1 dephosphorylation coincided with ERK1/2 phosphorylation that accompanies BAY 11-7085-induced synovial fibroblasts apoptosis. 15d-PGJ2, PGD2, and partially UO126, down-regulated ERK1/2 phosphorylation, protected cells from BAY 11-7085-induced apoptosis, and reversed both PPAR- dephosphorylation and degradation. Furthermore, PPAR- antagonist BADGE induced PPAR-1 degradation, ERK1/2 phosphorylation, and synovial fibroblasts apoptosis. The results presented suggest an anti-apoptotic role for PPAR-1 in synovial fibroblasts. Since apoptotic marker PARP is cleaved after PPAR-1 dephosphorylation but before PPAR-1 degradation, dephosphorylation event might be enough to mediate BAY 11-7085-induced apoptosis in synovial fibroblasts.

Received for publication, November 30, 2005 , and in revised form, June 6, 2006.

^* This work was supported by the Fond d'Investissement de Recherche Scientifique (FIRS) credit 4774 (CHU Sart-Tilman). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Dept. of Rheumatology, CHU Sart-Tilman B35, 4000 Liège, Belgium. Tel.: 32-4-366-72-29; Fax: 32-4-366-70-16; E-mail: Michel.Malaise{at}ulg.ac.be.

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