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, Catherine C. Thompson

Research output: Contribution to journalArticle

165 Citations (Scopus)

Abstract

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, RORα. 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 RORα 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.

Original languageEnglish (US)
Pages (from-to)38665-38674
Number of pages10
JournalJournal of Biological Chemistry
Volume278
Issue number40
DOIs
StatePublished - Oct 3 2003

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Co-Repressor Proteins
Calcitriol Receptors
Hair
Proteins
Cytoplasmic and Nuclear Receptors
Thyroid Hormone Receptors
Transcriptional Activation
Genes
Orphan Nuclear Receptors
Ligands
Retinoid X Receptors
Hair Follicle
Alopecia
Gene expression
In Situ Hybridization
Rats
Skin
Transcription Factors
Chemical activation

ASJC Scopus subject areas

  • Biochemistry

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Physical and functional interaction between the vitamin D receptor and hairless corepressor, two proteins required for hair cycling. / Hsieh, Jui-Cheng; Sisk, Jeanne M.; Jurutka, Peter W.; Haussler, Carol A.; Slater, Stephanie A.; Haussler, Mark R; Thompson, Catherine C.

In: Journal of Biological Chemistry, Vol. 278, No. 40, 03.10.2003, p. 38665-38674.

Research output: Contribution to journalArticle

Hsieh, Jui-Cheng ; Sisk, Jeanne M. ; Jurutka, Peter W. ; Haussler, Carol A. ; Slater, Stephanie A. ; Haussler, Mark R ; Thompson, Catherine C. / Physical and functional interaction between the vitamin D receptor and hairless corepressor, two proteins required for hair cycling. In: Journal of Biological Chemistry. 2003 ; Vol. 278, No. 40. pp. 38665-38674.
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