Hairless suppresses vitamin D receptor transactivation in human keratinocytes.
The vitamin D receptor (VDR) and its ligand 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] are required for normal keratinocyte differentiation. Both the epidermis and the hair follicle are disrupted in VDR-null mice. Hairless (Hr), a presumptive transcription factor with no known ligand, when mutated, disrupts hair follicle cycling similar to the effects of VDR mutations. Hr, like VDR, is found in the nuclei of keratinocytes in both epidermis and hair follicle. To investigate the potential interaction between Hr and VDR on keratinocyte differentiation, we examined the effect of Hr expression on vitamin D-responsive genes in normal human keratinocytes. Inhibition of Hr expression in keratinocytes potentiated the induction of vitamin D-responsive genes, including involucrin, transglutaminase, phospholipase C-gamma1, and 25-hydroxyvitamin D-24-hydroxylase (24-hydroxylase) by 1,25(OH)2D3. Overexpression of Hr in human keratinocytes suppressed the induction of these vitamin D-responsive genes by 1,25(OH)2D3. Coimmunoprecipitation, DNA mobility shift assays, and chromatin immunoprecipitation revealed that Hr binds to VDR in human keratinocytes. Hr binding to the VDR was eliminated by 1,25(OH)2D3, which recruited the coactivator vitamin D receptor-interacting protein 205 (DRIP205) to the VDR/vitamin D response element complex. These data indicate that Hr functions as a corepressor of VDR to block 1,25(OH)2D3 action on keratinocytes.
Xie
Zhongjian
Z
Endocrine Unit, Veterans Affairs Medical Center, San Francisco, California 94121, USA. zjxie@itsa.ucsf.edu
Chang
Sandra
S
Oda
Yuko
Y
Bikle
Daniel D
DD
D000818:Animals; D002460:Cell Line; D002843:Chromatin / Q000235:genetics / Q000648:ultrastructure; D017931:DNA Primers; D006801:Humans; D015603:Keratinocytes / Q000502:physiology*; D007668:Kidney; D016133:Polymerase Chain Reaction; D018167:Receptors, Calcitriol / Q000235:genetics*; D014157:Transcription Factors / Q000502:physiology*; D015533:Transcriptional Activation; D016335:Zinc Fingers
D002843:Chromatin; D017931:DNA Primers; C490267:HR protein, human; D018167:Receptors, Calcitriol; D014157:Transcription Factors