Ligand-independent regulation of the hairless promoter by vitamin D receptor.
The characteristic alopecia associated with mutations in the hairless (hr) and vitamin D receptor (VDR) genes defines the resulting genetic disorders, known as atrichia and VDRRIIa rickets, as phenocopies. In both cases, the separation of the dermal papilla from the regressing hair follicle at the onset of the first catagen phase of the hair cycle and the development of dermal cysts and utricules subsequent to mutation of either gene suggests that their activities affect the same regulatory pathways. VDR functions as a hormonally activated transcription factor, and a role in transcription has been postulated for Hr due in part to its nuclear localization and homology with the GATA-1 zinc-finger domain. Therefore, we examined the hypothesis that VDR and Hr have a direct regulatory effect on each other via a transcriptional mechanism. Ectopic expression of the VDR repressed hr promoter activity in HaCaT cells and primary human keratinocytes (PHKs). While this repression occurs in the absence of 1,25 dihydroxyvitamin D3 (D3), the addition of ligand greatly augments the effect. However, we also demonstrate the rare phenomenon of ligand-independent promoter transactivation by VDR. We show that the full-length promoter is transactivated by VDR in a ligand-independent and cell type-specific manner, suggesting that direct transcriptional regulation of hr by the VDR accounts in part for the phenotypic overlap between atrichia and VDRRIIa rickets.
Engelhard
Andrew
A
Department of Dermatology, Columbia University, New York, NY, USA.
Bauer
Robert C
RC
Casta
Alexandre
A
Djabali
Karima
K
Christiano
Angela M
AM
D000818:Animals; D001483:Base Sequence; D045744:Cell Line, Tumor; D017931:DNA Primers; D006801:Humans; D008024:Ligands; D051379:Mice; D041681:NIH 3T3 Cells; D011401:Promoter Regions, Genetic; D018167:Receptors, Calcitriol / Q000502:physiology*; D014157:Transcription Factors / Q000235:genetics*
D017931:DNA Primers; D008024:Ligands; D018167:Receptors, Calcitriol; D014157:Transcription Factors; C088661:hr protein, mouse