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J. Biol. Chem., Vol. 282, Issue 41, 29987-29997, October 12, 2007

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p21^WAF1/CIP1 Is a Common Transcriptional Target of Retinoid Receptors

PLEIOTROPIC REGULATORY MECHANISM THROUGH RETINOIC ACID RECEPTOR (RAR)/RETINOID X RECEPTOR (RXR) HETERODIMER AND RXR/RXR HOMODIMER^*

From the NCI, National Institutes of Health, Bethesda, Maryland 20892-4255

The divergent response and the molecular mechanisms underlying the anti-cancer effects of retinoid X receptor (RXR) ligand (rexinoid) therapy are poorly understood. This study demonstrates that ligand-activated RXR homodimer facilitated G₁ arrest by up-regulation of p21 in vitro and in vivo but failed to induce G₁ arrest when p21 expression was blocked by p21 small interfering RNA. RXR ligand-dependent p21 up-regulation was transcriptionally controlled through the direct binding of RXR homodimers to two consecutive retinoid X response elements in the p21 promoter. Structural overlap of a retinoic acid response element with these retinoid X response elements led to a high affinity binding of retinoic acid receptor/RXR heterodimer to the retinoic acid response element, resulting in the prevention of RXR ligand-mediated p21 transactivation. These data show that p21 is a potential and novel molecular target for RXR ligand-mediated anti-cancer therapy and that the expression level of retinoic acid receptor and RXR in tumors may be crucial to induce p21-mediated cell growth arrest in RXR ligand therapy.

Received for publication, February 27, 2007 , and in revised form, July 9, 2007.

^* This research was supported by the Intramural Research Program of the NCI, National Institutes of Health, Center for Cancer Research. 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental data.

² Present address: Dept. of Human Nutrition, Bloomberg School of Public Health, The Johns Hopkins University, Baltimore, MD 21205.

¹ To whom correspondence should be addressed: University of Texas Health Science Center, Institute of Molecular Medicine, 1825 Herman Pressler, Rm. 537C, Houston, TX 77030. Tel.: 713-500-2497; E-mail: Takemi.Tanaka{at}uth.tmc.edu.

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