title: Vitamin D receptor-mediated control of Soggy, Wise, and Hairless gene expression in keratinocytes.
abstract: The vitamin D receptor (VDR), but not its hormonal ligand, 1,25-dihydroxyvitamin D3 (1,25D), is required for the progression of the mammalian hair cycle. We studied three genes relevant to hair cycle signaling, DKKL1 (Soggy), SOSTDC1 (Wise), and HR (Hairless), to determine whether their expression is regulated by VDR and/or its 1,25D ligand. DKKL1 mRNA was repressed 49-72% by 1,25D in primary human and CCD-1106 KERTr keratinocytes; a functional vitamin D responsive element (VDRE) was identified at -9590 bp in murine Soggy. Similarly, SOSTDC1 mRNA was repressed 41-59% by 1,25D in KERTr and primary human keratinocytes; a functional VDRE was located at -6215 bp in human Wise. In contrast, HR mRNA was upregulated 1.56- to 2.77-fold by 1,25D in primary human and KERTr keratinocytes; a VDRE (TGGTGAgtgAGGACA) consisting of an imperfect direct repeat separated by three nucleotides (DR3) was identified at -7269 bp in the human Hairless gene that mediated dramatic induction, even in the absence of 1,25D ligand. In parallel, a DR4 thyroid hormone responsive element, TGGTGAggccAGGACA, was identified at +1304 bp in the human HR gene that conferred tri-iodothyronine (T3)-independent transcriptional activation. Because the thyroid hormone receptor controls HR expression in the CNS, whereas VDR functions in concert with the HR corepressor specifically in skin, a model is proposed wherein unliganded VDR upregulates the expression of HR, the gene product of which acts as a downstream comodulator to feedback-repress DKKL1 and SOSTDC1, resulting in integration of bone morphogenic protein and Wnt signaling to drive the mammalian hair cycle and/or influencing epidermal function.
authors.affiliation: Department of Basic Medical Sciences, University of Arizona College of Medicine, 425 North 5th Street, Phoenix, Arizona 85004-2157, USA School of Mathematical and Natural Sciences, Arizona State University, Phoenix, Arizona 85306, USA.
authors.forename: Jui-Cheng
authors.initials: JC
authors.lastname: Hsieh
authors.forename: Rudolf C
authors.initials: RC
authors.lastname: Estess
authors.forename: Ichiro
authors.initials: I
authors.lastname: Kaneko
authors.forename: G Kerr
authors.initials: GK
authors.lastname: Whitfield
authors.forename: Peter W
authors.initials: PW
authors.lastname: Jurutka
authors.forename: Mark R
authors.initials: MR
authors.lastname: Haussler
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D019556:COS Cells; D018938:Caco-2 Cells; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D047908:Intracellular Signaling Peptides and Proteins; D015603:Keratinocytes / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D011506:Proteins / Q000235:genetics* / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D018167:Receptors, Calcitriol / Q000502:physiology*; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D030181:Vitamin D Response Element / Q000235:genetics
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C577596:DKKL1 protein, human; C490267:HR protein, human; D036341:Intercellular Signaling Peptides and Proteins; D047908:Intracellular Signaling Peptides and Proteins; D009687:Nuclear Proteins; D011506:Proteins; D016601:RNA-Binding Proteins; D018167:Receptors, Calcitriol; C480733:SOSTDC1 protein, human; D014157:Transcription Factors
keywords: gene regulation; hormone receptors; skin; transcription factors; vitamin D