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J. Biol. Chem., Vol. 282, Issue 7, 4417-4426, February 16, 2007

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Association with Coregulators Is the Major Determinant Governing Peroxisome Proliferator-activated Receptor Mobility in Living Cells^*

Cicerone Tudor¹, Jérôme N. Feige¹, Harikishore Pingali^¶, Vidya Bhushan Lohray^¶, Walter Wahli, Béatrice Desvergne, Yves Engelborghs², and Laurent Gelman³

From the Laboratory of Biomolecular Dynamics, Katholieke Universiteit, Leuven B-3001, Belgium, Center for Integrative Genomics, National Research Center "Frontiers in Genetics," University of Lausanne, Lausanne CH-1015, Switzerland, and ^¶Zydus Research Centre, Ahmedabad 382210, India

The nucleus is an extremely dynamic compartment, and protein mobility represents a key factor in transcriptional regulation. We showed in a previous study that the diffusion of peroxisome proliferator-activated receptors (PPARs), a family of nuclear receptors regulating major cellular and metabolic functions, is modulated by ligand binding. In this study, we combine fluorescence correlation spectroscopy, dual color fluorescence cross-correlation microscopy, and fluorescence resonance energy transfer to dissect the molecular mechanisms controlling PPAR mobility and transcriptional activity in living cells. First, we bring new evidence that in vivo a high percentage of PPARs and retinoid X receptors is associated even in the absence of ligand. Second, we demonstrate that coregulator recruitment (and not DNA binding) plays a crucial role in receptor mobility, suggesting that transcriptional complexes are formed prior to promoter binding. In addition, association with coactivators in the absence of a ligand in living cells, both through the N-terminal AB domain and the AF-2 function of the ligand binding domain, provides a molecular basis to explain PPAR constitutive activity.

Received for publication, August 25, 2006 , and in revised form, December 12, 2006.

^* This work was supported by grants from the National Research Project 50, the Swiss National Science Foundation, the Etat de Vaud (to W. W. and B. D.), the Research Council (to C. T.), Grant GOA 2006/09 (to Y. E.) from the Katholieke Universiteit Leuven, and Project G.0584.06 from the Fund for Scientific Research Flanders (to Y. E.). 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 Both authors contributed equally to this work.

² To whom correspondence may be addressed: Laboratory of Biomolecular Dynamics, Katholieke Universiteit Leuven, Celestjnenlaan 200G, B-3001 Leuven, Belgium. Tel.: 32-16-32-71-60; Fax: 32-16-32-79-74; E-mail: yves.engelborghs{at}fys.kuleuven.be. ³ To whom correspondence may be addressed: Friedrich Miescher Institute, WRO 1066.0.52, Maulbeerstrasse 66, CH-4058 Basel, Switzerland. Tel.: 41-61-69-78-590; E-mail: laurent.gelman{at}fmi.ch.

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