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J. Biol. Chem., Vol. 281, Issue 26, 17856-17863, June 30, 2006

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The Glucocorticoid Receptor Represses Cyclin D1 by Targeting the Tcf--Catenin Complex^*

Sachiko Takayama, Inez Rogatsky, Leslie E. Schwarcz, and Beatrice D. Darimont¹

From the Institute of Molecular Biology and Department of Chemistry, University of Oregon, Eugene, Oregon 97403-1229 and Hospital of Special Surgery and Department of Microbiology and Immunology, Weill Medical College of Cornell University, New York, New York 10021

The ability of glucocorticoids (GCs) to regulate cell proliferation plays an important role in their therapeutic use. The canonical Wnt pathway, which promotes the proliferation of many cancers and differentiated tissues, is an emerging target for the actions of GCs, albeit existing links between these signaling pathways are indirect. By screening known Wnt target genes for their ability to respond differently to GCs in cells whose proliferation is either positively or negatively regulated by GCs, we identified c-myc, c-jun, and cyclin D1, which encode rate-limiting factors for G₁ progression of the cell cycle. Here we show that in U2OS/GR cells, which are growth-arrested by GCs, the glucocorticoid receptor (GR) represses cyclin D1 via Tcf--catenin, the transcriptional effector of the canonical Wnt pathway. We demonstrate that GR can bind -catenin in vitro, suggesting that GC and Wnt signaling pathways are linked directly through their effectors. Down-regulation of -catenin by RNA interference impeded the expression of cyclin D1 but not of c-myc or c-jun and had no significant effect on the proliferation of U2OS/GR cells. Although these results revealed that -catenin and cyclin D1 are not essential for the regulation of U2OS/GR cell proliferation, considering the importance of the Wnt pathway for proliferation and differentiation of other cells, the repression of Tcf--catenin activity by GR could open new possibilities for tissue-selective GC therapies.

Received for publication, March 10, 2006 , and in revised form, April 27, 2006.

^* This work was supported by American Heart Association Research Grant 0060423Z (to B. D.) and by a traineeship (to L. S.) from National Institutes of Health (NIH) Grant 5 T32 GM07413. The original microarray data collection was funded by NIH Grant RO1 CA20535 (to K. R. Yamamoto). 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 To whom correspondence should be addressed: Institute of Molecular Biology, University of Oregon, Eugene, OR 97403-1229. Tel.: 541-346-5265; Fax: 541-346-5891; E-mail: bead{at}molbio.uoregon.edu.

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