Evidence for 1,25-dihydroxyvitamin D3-independent transactivation by the vitamin D receptor: uncoupling the receptor and ligand in keratinocytes.

Evidence for 1,25-dihydroxyvitamin D3-independent transactivation by the vitamin D receptor: uncoupling the receptor and ligand in keratinocytes. Research Abstract Details 

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Evidence for 1,25-dihydroxyvitamin D3-independent transactivation by the vitamin D receptor: uncoupling the receptor and ligand in keratinocytes. Abstract Text:

Tara I Ellison,Richard L Eckert,Paul N MacDonald,

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 1alpha-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 1alpha-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.

Evidence for 1,25-dihydroxyvitamin D3-independent transactivation by the vitamin D receptor: uncoupling the receptor and ligand in keratinocytes. Publishing Authors By Initials

TI Ellison,RL Eckert,PN MacDonald,

For similar genetic processes: gene expression: transcription, genetic research abstracts see: genetic processes: gene expression: transcription, genetic research

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Evidence for 1,25-dihydroxyvitamin D3-independent transactivation by the vitamin D receptor: uncoupling the receptor and ligand in keratinocytes. Journal Published:

PUBLICATION TYPE: Research Support, N.I.H., Extr

Journal: The Journal of biological chemistry

VOLUME: 282

Page Numbers: 10953-62

Journal Abbreviation:

ISSN: 0021-9258

DAY: 19

MONTH: 02

YEAR: 2007

Evidence for 1,25-dihydroxyvitamin D3-independent transactivation by the vitamin D receptor: uncoupling the receptor and ligand in keratinocytes. Information

Number of References:

LANGUAGE: eng

NlmUniqueID: 2985121

Evidence for 1,25-dihydroxyvitamin D3-independent transactivation by the vitamin D receptor: uncoupling the receptor and ligand in keratinocytes. Keywords Mesh Terms:

KEYWORDS: Transcription, Genetic

MESH TERMS: genetics

Chemical & Substance for Abstract: Evidence for 1,25-dihydroxyvitamin D3-independent transactivation by the vitamin D receptor: uncoupling the receptor and ligand in keratinocytes. Information

Substance Name: vitamin D 24-hydroxylase

Registry Number: EC 1.14.-

Grant and Affiliation Information for Evidence for 1,25-dihydroxyvitamin D3-independent transactivation by the vitamin D receptor: uncoupling the receptor and ligand in keratinocytes.

AFFILIATION: Department of Pharmacology, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, USA.

Country: United States

AGENCY: United States NIGMS

GRANT: T32GM 08803

ACRONYM: GM

MEDLINETA: J Biol Chem

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