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J. Biol. Chem., Vol. 280, Issue 18, 17880-17890, May 6, 2005

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Fluorescence Imaging Reveals the Nuclear Behavior of Peroxisome Proliferator-activated Receptor/Retinoid X Receptor Heterodimers in the Absence and Presence of Ligand^*

Jérôme N. Feige, Laurent Gelman, Cicerone Tudor¶, Yves Engelborghs¶, Walter Wahli, and Béatrice Desvergne||

From the Center for Integrative Genomics, NCCR Frontiers in Genetics, University of Lausanne, CH-1015 Lausanne, Switzerland and the ^¶Laboratory of Biomolecular Dynamics, Katholieke Universiteit Leuven, B3001 Leuven, Belgium

In a global approach combining fluorescence recovery after photobleaching (FRAP), fluorescence correlation spectroscopy (FCS), and fluorescence resonance energy transfer (FRET), we address the behavior in living cells of the peroxisome proliferator-activated receptors (PPARs), a family of nuclear receptors involved in lipid and glucose metabolism, inflammation control, and wound healing. We first demonstrate that unlike several other nuclear receptors, PPARs do not form speckles upon ligand activation. The subnuclear structures that may be observed under some experimental conditions result from overexpression of the protein and our immunolabeling experiments suggest that these structures are subjected to degradation by the proteasome. Interestingly and in contrast to a general assumption, PPARs readily heterodimerize with retinoid X receptor (RXR) in the absence of ligand in living cells. PPAR diffusion coefficients indicate that all the receptors are engaged in complexes of very high molecular masses and/or interact with relatively immobile nuclear components. PPARs are not immobilized by ligand binding. However, they exhibit a ligand-induced reduction of mobility, probably due to enhanced interactions with cofactors and/or chromatin. Our study draws attention to the limitations and pitfalls of fluorescent chimera imaging and demonstrates the usefulness of the combination of FCS, FRAP, and FRET to assess the behavior of nuclear receptors and their mode of action in living cells.

Received for publication, January 21, 2005 , and in revised form, February 23, 2005.

^* This work was supported by grants from the Université Lausanne/Ecole Polytechnique Fédérale Lausanne fund, the National Research Project 50, the Swiss National Science Foundation, and the Etat de Vaud (to W. W. and B. D.) and by the Research Council (to C. T.) and the grant GOA 2001/2 (to Y. E.) of the Katholieke Universiteit Leuven. 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.

This article was selected as a Paper of the Week.

These authors contributed equally to this work.

^|| To whom correspondence should be addressed: Center for Integrative Genomics, Université de Lausanne, Batiment de Biologie, CH-1015 Lausanne, Switzerland. Tel.: 41-21-692-41-40; Fax: 41-21-692-41-15; E-mail: beatrice.desvergne{at}unil.ch.

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