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J. Biol. Chem., Vol. 278, Issue 43, 41589-41592, October 24, 2003

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Retinoic Acid Is a High Affinity Selective Ligand for the Peroxisome Proliferator-activated Receptor /^*

Natacha Shaw, Morten Elholm, and Noa Noy

From the Division of Nutritional Sciences, Cornell University, Ithaca, New York 14853

Retinoic acid (RA) modulates transcription of numerous target genes, thereby regulating a myriad of biological processes. It is well established that RA functions by activating retinoic acid receptors (RARs), which, in turn, control cell differentiation, proliferation, and apoptosis. However, perplexing reports of diverse and sometime opposing actions of RA have been published. Hence, while RA induces apoptosis and inhibits cell growth in some settings, it potentiates proliferation and acts as an anti-apoptotic agent in others. These observations raise the possibility that signaling pathways other than RAR may be involved in mediating RA activities. Here we show that RA is a high affinity ligand for another nuclear receptor, namely the orphan receptor peroxisome proliferator-activated receptor (PPAR) /. We demonstrate that while RA does not activate PPAR and PPAR, it binds to PPAR/ with nanomolar affinity, modulates the conformation of the receptor, promotes interaction with the coactivator SRC-1, and efficiently activates PPAR/-mediated transcription. Transcriptional signaling by RA is thus exerted by a dual pathway, providing a rationale for understanding divergent cellular responses to this hormone.

Received for publication, August 18, 2003 , and in revised form, September 2, 2003.

^* This work was supported by Grants CA68150 and DK060684 from the National Institutes of Health. 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.

To whom correspondence should be addressed: 225 Savage Hall, Cornell University, Ithaca, NY 14853. Tel.: 607-255-2490; Fax: 607-255-1033; E-mail: nn14{at}cornell.edu.

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