Reciprocal role of vitamin D receptor on β-catenin regulated keratinocyte proliferation and differentiation

The active metabolite of vitamin D, 1,25-dihydroxyvitamin D3 (1,25(OH)(2)D-3), suppresses the proliferation while promoting the differentiation of keratinocytes through the vitamin D receptor (VDR). beta-Catenin, on the other hand, promotes proliferation and blocks epidermal differentiation, although it stimulates hair follicle differentiation. In intestinal epithelia VDR binds beta-catenin and blocks its proliferative effects. In this study we investigated the role of 1,25(OH)(2)D-3/VDR on beta-catenin regulated gene transcription during keratinocyte proliferation and differentiation. 1,25(OH)(2)D-3 suppressed promoter reporter activity driven by synthetic and natural TCF/beta-catenin response elements. Overexpression of VDR further suppressed these TCF/beta-catenin promoter activities. 1,25(OH)(2)D-3 also suppressed the mRNA expression of the beta-catenin regulated gene Gli1 through VDR. These data were consistent with our previous observations that VDR silencing resulted in keratinocyte hyperproliferation with increased expression of Gli1 in vitro, whereas VDR null skin showed hyperproliferation in vivo. In contrast, 1,25(OH)(2)D-3 induced expression of another beta-catenin regulated gene, PADI1, important for both epidermal and hair follicle differentiation. Deletion of VDR resulted in defects in hair differentiation in vivo, with decreased expression of beta-catenin regulated hair differentiation genes such as PADI1, hair keratin KRT31 and calcium binding protein S100a3. These genes possess vitamin D response elements (VDRE) adjacent to TCF/beta-catenin response elements and are regulated by both VDR and beta-catenin signaling. Therefore, we propose that VDR and beta-catenin interact reciprocally to promote VDR stimulation of genes involved with differentiation that contain both VDR and beta-catenin response elements while inhibiting beta-catenin stimulation of genes involved with proliferation. Thus the major finding of this study is that while 1,25(OH)(2)D-3/VDR inhibits the actions of beta-catenin to promote keratinocyte proliferation, 1,25(OH)(2)D-3/VDR promotes the ability of beta-catenin to stimulate hair follicle differentiation. This article is part of a Special Issue entitled '16th Vitamin D Workshop'. (C) 2013 Elsevier Ltd. All rights reserved.