Department of Medicine, University of California, San Francisco, San Francisco and Veterans Affairs Medical Center, San Francisco, CA 94121, USA; School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China.
Department of Medicine, University of California, San Francisco, San Francisco and Veterans Affairs Medical Center, San Francisco, CA 94121, USA.
J Steroid Biochem Mol Biol. 2014 Oct;144 Pt A:237-41. doi: 10.1016/j.jsbmb.2013.11.002. Epub 2013 Nov 12.
The active metabolite of vitamin D, 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), suppresses the proliferation while promoting the differentiation of keratinocytes through the vitamin D receptor (VDR). β-Catenin, on the other hand, promotes proliferation and blocks epidermal differentiation, although it stimulates hair follicle differentiation. In intestinal epithelia VDR binds β-catenin and blocks its proliferative effects. In this study we investigated the role of 1,25(OH)2D3/VDR on β-catenin regulated gene transcription during keratinocyte proliferation and differentiation. 1,25(OH)2D3 suppressed promoter reporter activity driven by synthetic and natural TCF/β-catenin response elements. Over-expression of VDR further suppressed these TCF/β-catenin promoter activities. 1,25(OH)2D3 also suppressed the mRNA expression of the β-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)2D3 induced expression of another β-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 β-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/β-catenin response elements and are regulated by both VDR and β-catenin signaling. Therefore, we propose that VDR and β-catenin interact reciprocally to promote VDR stimulation of genes involved with differentiation that contain both VDR and β-catenin response elements while inhibiting β-catenin stimulation of genes involved with proliferation. Thus the major finding of this study is that while 1,25(OH)2D3/VDR inhibits the actions of β-catenin to promote keratinocyte proliferation, 1,25(OH)2D3/VDR promotes the ability of β-catenin to stimulate hair follicle differentiation. This article is part of a Special Issue entitled '16th Vitamin D Workshop'.
维生素 D 的活性代谢物 1,25-二羟维生素 D3（1,25(OH)2D3）通过维生素 D 受体（VDR）抑制角质形成细胞的增殖，同时促进其分化。β-连环蛋白（β-catenin）则通过刺激毛囊分化来促进增殖并阻断表皮分化，尽管它也能刺激毛囊分化。在肠道上皮中，VDR 结合 β-连环蛋白并阻断其增殖作用。在这项研究中，我们研究了 1,25(OH)2D3/VDR 在角质形成细胞增殖和分化过程中对 β-连环蛋白调节基因转录的作用。1,25(OH)2D3 抑制合成和天然 TCF/β-连环蛋白反应元件驱动的启动子报告基因活性。VDR 的过表达进一步抑制了这些 TCF/β-连环蛋白启动子活性。1,25(OH)2D3 还通过 VDR 抑制 β-连环蛋白调节基因 Gli1 的 mRNA 表达。这些数据与我们之前的观察结果一致，即 VDR 沉默导致体外角质形成细胞过度增殖，Gli1 表达增加，而 VDR 缺失皮肤在体内表现出过度增殖。相比之下，1,25(OH)2D3 诱导另一个β-连环蛋白调节基因 PADI1 的表达，这对表皮和毛囊分化都很重要。VDR 缺失导致体内毛发分化缺陷，β-连环蛋白调节的毛发分化基因如 PADI1、毛发角蛋白 KRT31 和钙结合蛋白 S100a3 的表达减少。这些基因具有维生素 D 反应元件（VDRE），位于 TCF/β-连环蛋白反应元件旁边，受 VDR 和 β-连环蛋白信号的共同调节。因此，我们提出 VDR 和 β-连环蛋白相互作用，促进包含 VDR 和 β-连环蛋白反应元件的参与分化的基因的 VDR 刺激，同时抑制参与增殖的基因的 β-连环蛋白刺激。因此，本研究的主要发现是，1,25(OH)2D3/VDR 抑制β-连环蛋白促进角质形成细胞增殖的作用，而 1,25(OH)2D3/VDR 促进β-连环蛋白刺激毛囊分化的能力。本文是特刊“第 16 届维生素 D 研讨会”的一部分。
