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J. Biol. Chem., Vol. 278, Issue 40, 38665-38674, October 3, 2003

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Physical and Functional Interaction between the Vitamin D Receptor and Hairless Corepressor, Two Proteins Required for Hair Cycling^*

Jui-Cheng Hsieh  , Jeanne M. Sisk  ¶, Peter W. Jurutka , Carol A. Haussler , Stephanie A. Slater , Mark R. Haussler  and Catherine C. Thompson ¶ ||

From the Department of Biochemistry and Molecular Biophysics, University of Arizona College of Medicine, Tucson, Arizona 85724 and ^¶Kennedy Krieger Institute and Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205

Both the vitamin D receptor (VDR) and hairless (hr) genes play a role in the mammalian hair cycle, as inactivating mutations in either result in total alopecia. VDR is a nuclear receptor that functions as a ligand-activated transcription factor, whereas the hairless gene product (Hr) acts as a corepressor of both the thyroid hormone receptor (TR) and the orphan nuclear receptor, ROR. In the present study, we show that VDR-mediated transactivation is strikingly inhibited by coexpression of rat Hr. The repressive effect of Hr is observed on both synthetic and naturally occurring VDR-responsive promoters and also when VDR-mediated transactivation is augmented by overexpression of its heterodimeric partner, retinoid X receptor. Utilizing in vitro pull down methods, we find that Hr binds directly to VDR but insignificantly to nuclear receptors that are not functionally repressed by Hr. Coimmunoprecipitation data demonstrate that Hr and VDR associate in a cellular milieu, suggesting in vivo interaction. The Hr contact site in human VDR is localized to the central portion of the ligand binding domain, a known corepressor docking region in other nuclear receptors separate from the activation function-2 domain. Coimmunoprecipitation and functional studies of Hr deletants reveal that VDR contacts a C-terminal region of Hr that includes motifs required for TR and ROR binding. Finally, in situ hybridization analysis of hr and VDR mRNAs in mouse skin demonstrates colocalization in cells of the hair follicle, consistent with a hypothesized intracellular interaction between these proteins to repress VDR target gene expression, in vivo.

Received for publication, May 9, 2003 , and in revised form, June 27, 2003.

^* This work was supported in part by National Institutes of Health Grants DK33351 and DK063930 (to M. R. H.) and NS41313 (to C. C. T.). 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.

These authors contributed equally to this work.

^|| To whom correspondence should be addressed. Tel.: 443-923-2689; Fax: 443-923-2695; E-mail: thompsonc{at}kennedykrieger.org.

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