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Papers In Press, published online ahead of print July 7, 2003
J. Biol. Chem, 10.1074/jbc.M304886200
Submitted on May 9, 2003
Revised on June 27, 2003
Accepted on July 3, 2003
Kennedy Krieger Institute, Baltimore, MD 21205
Corresponding Author: thompsonc{at}kennedykrieger.org
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 co-expression 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 pulldown 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 which 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.
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