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The Protein Kinase C Signaling Pathway Regulates a Molecular Switch between Transactivation and Transrepression Activity of the Peroxisome Proliferator-Activated Receptor

Institut National de la Santé et de la Recherche Médicale, Unité de Recherche 545, Département d’Athérosclérose, Institut Pasteur de Lille, 59019 Lille, and Faculté de Pharmacie, Université de Lille II, 59000 Lille, France

Address all correspondence and requests for reprints to: Dr. Corine Glineur, UR 545 Institut National de la Santé et de la Recherche Médicale, Département d’Athérosclérose, Institut Pasteur de Lille, 1 rue du Pr. Calmette, 59019 Lille, France. E-mail: Corine.Glineur{at}pasteur-lille.fr.

Peroxisome proliferator-activated receptor (PPAR) is a nuclear receptor implicated in several physiological processes such as lipid and lipoprotein metabolism, glucose homeostasis, and the inflammatory response. PPAR is activated by natural fatty acids and synthetic compounds like fibrates. PPAR activity has been shown to be modulated by its phosphorylation status. PPAR is phosphorylated by kinases such as the MAPKs and cAMP-activated protein kinase A. In this report, we show that protein kinase C (PKC) inhibition impairs ligand-activated PPAR transcriptional activity. Furthermore, PKC inhibition decreases PPAR ligand-induction of its target genes including PPAR itself and carnitine palmitoyltransferase I. By contrast, PKC inhibition enhances PPAR transrepression properties as demonstrated using the fibrinogen-ß gene as model system. Finally, PKC inhibition decreases PPAR phosphorylation activity of hepatocyte cell extracts. In addition, PPAR purified protein is phosphorylated in vitro by recombinant PKC and ßII. The replacement of serines 179 and 230 by alanine residues reduces the phosphorylation of the PPAR protein. The PPAR S179A-S230A protein displays an impaired ligand-induced transactivation activity and an enhanced trans-repression activity. Altogether, our data indicate that the PKC signaling pathway acts as a molec-ular switch dissociating the transactivation and transrepression functions of PPAR, which involved phosphorylation of serines 179 and 230.

NURSA Molecule Pages Link:

Nuclear Receptors:   PPARα

Ligands:   GW 7647

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