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DNA Binding Properties of Peroxisome Proliferator-activated Receptor Subtypes on Various Natural Peroxisome Proliferator Response Elements

1997; Elsevier BV; Volume: 272; Issue: 40 Linguagem: Inglês

10.1074/jbc.272.40.25252

1083-351X

Cristiana E. Juge-Aubry, Agnès Pernin, Tatiana Favez, Albert Burger, Walter Wahli, C. A. Meier, Béatrice Desvergne,

Cancer, Hypoxia, and Metabolism

The three subtypes of the peroxisome proliferator-activated receptors (PPARα, β/δ, and γ) form heterodimers with the 9- cis -retinoic acid receptor (RXR) and bind to a common consensus response element, which consists of a direct repeat of two hexanucleotides spaced by one nucleotide (DR1). As a first step toward understanding the molecular mechanisms determining PPAR subtype specificity, we evaluated by electrophoretic mobility shift assays the binding properties of the three PPAR subtypes, in association with either RXRα or RXRγ, on 16 natural PPAR response elements (PPREs). The main results are as follows. (i) PPARγ in combination with either RXRα or RXRγ binds more strongly than PPARα or PPARβ to all natural PPREs tested. (ii) The binding of PPAR to strong elements is reinforced if the heterodimerization partner is RXRγ. In contrast, weak elements favor RXRα as heterodimerization partner. (iii) The ordering of the 16 natural PPREs from strong to weak elements does not depend on the core DR1 sequence, which has a relatively uniform degree of conservation, but correlates with the number of identities of the 5′-flanking nucleotides with respect to a consensus element. This 5′-flanking sequence is essential for PPARα binding and thus contributes to subtype specificity. As a demonstration of this, the PPARγ-specific element ARE6 PPRE is able to bind PPARα only if its 5′-flanking region is exchanged with that of the more promiscuous HMG PPRE.