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J. Biol. Chem., Vol. 282, Issue 15, 10953-10962, April 13, 2007

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Evidence for 1,25-Dihydroxyvitamin D₃-independent Transactivation by the Vitamin D Receptor

UNCOUPLING THE RECEPTOR AND LIGAND IN KERATINOCYTES^*

Tara I. Ellison¹, Richard L. Eckert, and Paul N. MacDonald²

From the Departments of Pharmacology and Physiology and Biophysics, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106

The vitamin D endocrine system plays critical although poorly understood roles in skin. Vitamin D receptor (VDR) knock-out (VDRKO) mice have defects in hair follicle cycling and keratinocyte proliferation leading to epidermal thickening, dermal cyst formation, and alopecia. Surprisingly, skin defects are not apparent in mice lacking 25-hydroxyvitamin D 1-hydroxylase, the enzyme required for 1,25-dihydroxyvitamin D₃ (1,25(OH)₂D₃) hormone biosynthesis. These disparate phenotypes indicate that VDR effects in skin are independent of the 1,25(OH)₂D₃ ligand. However, cellular or molecular data supporting this hypothesis are lacking. Here, we show transcriptional activation of the vitamin D-responsive 24-hydroxylase promoter by VDR in primary keratinocytes that is independent of the 1,25(OH)₂D₃ ligand. This activity required functional vitamin D-responsive promoter elements as well as an intact VDR DNA binding domain and thus could not be distinguished from 1,25(OH)₂D₃-dependent VDR transactivation. The 1,25(OH)₂D₃-independent activation of VDR was also observed in keratinocytes from 1-hydroxylase knock-out mice, indicating that it is not due to endogenous 1,25(OH)₂D₃ production. Mammalian two-hybrid studies showed strong, 1,25(OH)₂D₃-independent interaction between VDR and retinoid X receptors in primary keratinocytes, indicating that enhanced heterodimerization of these receptors was involved. Indeed, this 1,25(OH)₂D₃-independent VDR-RXR heterodimerization was sufficient to drive transactivation by VDR(L233S), an inactive ligand binding mutant of VDR that was previously shown to rescue the skin phenotype of VDR null mice. Cumulatively, these studies support the concept that transactivation by VDR in keratinocytes may be uncoupled from the 1,25(OH)₂D₃ ligand.

Received for publication, October 16, 2006 , and in revised form, February 2, 2007.

^* This work was supported by National Institutes of Health Grant RO1DK53980 and by a Pilot and Feasibility Component of the Skin Disease Research Center at Case Western Reserve University, P30 AR639750 (to P. N. M.). 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 Supported by NIGMS, National Institutes of Health, Institutional National Research Service Award T32GM 08803.

² To whom correspondence should be addressed: Dept. of Pharmacology, Case Western Reserve University, 10900 Euclid Ave., Cleveland, OH 44106. Tel.: 216-368-2466; Fax: 216-368-3395; E-mail: pnm2{at}case.edu.

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