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Peroxisome proliferator-activated receptors are key regulators in cell differentiation
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• Fibrates,.NSAIDs
@ PGJ2 1
.phosphorylation
RXR
Figure 1 : Activation ofppARs
(1). Extracellular ligands cross the p1asmic membrane and they bind to PPAR (1). Ligand binding
follows phosphory1ation (~:)or dephosphory1ation of receptor (2). Severa1 ligands, NSAIDs for
instance (e), have been shown to inhibit ppAR transcription by direct interaction with activated
receptor into the nucleus. Prostag1andin J2 derivative .) has a1so been shown to alter activation of
NFKl3 (3) by inhibiting phosphory1ation of IKl3 via IKl3 kinase. ppAR ligands cou1d a1so be
synthesize within the cell via the cyclooxygenase (@) or the 1ipoxygenase (0)pathway from
arachidonic or 1ino1eic acid (4,0 ). Finally ppAR form an heterodimer with RXR which bind to
PPRE on promotor of target genes (5). Subsequent1y, they increase or silence gene transcription
1eve1 by interacting with cofactors or corepressors. (abreviations : NSAID : nonsteroida1 anti
inflammatory drug; PGJ2 : 15-deoxy-ô-12, 14 prostag1andin J2; RXR, 9-cis retinoic acid receptor)
AGGTCAnnnTGACCT [17]. In addtion,
RXR as well as ppAR interact with the
thyroid hormone receptor suggesting that
crossta1k may exist between ppAR, RXR and
thyroid hormone receptor [18, 19]. Formation
of the heterodimer and subsequent
transcriptiona1 activation are 1iganddependent.
Ligand binding induces a
conformation change which places the
COOH-terminal helix 12 of the 1igand-binding
domain adjacent to a hydrophobic c1eft on the
surface of the 1igand-binding domain. This
occurs through direct protein interactions
with the LXXLL motif present in the
coactivator protein [20]. This modification
allows the binding of coactivators on the AF-2
domain 10ca1ised at the COOH-terminal ofthe
ligand-binding domain. As for other nuc1ear
receptors, coactivators consist of two genera1
classes [20, 21]: One class includes the steroid
receptor activator-1 family of proteins with
histone acetyltransferase activity which