Endocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA.
J Biol Chem. 2011 May 27;286(21):18444-51. doi: 10.1074/jbc.M110.188219. Epub 2011 Apr 6.
Ligand-independent actions of the vitamin D receptor (VDR) are required for normal post-morphogenic hair cycles; however, the molecular mechanisms by which the VDR exerts these actions are not clear. Previous studies demonstrated impaired regulation of the canonical Wnt signaling pathway in primary keratinocytes lacking the VDR. To identify the key effector of canonical Wnt signaling that interacts with the VDR, GST pulldown studies were performed. A novel interaction between the VDR and LEF1 (lymphoid enhancer-binding factor-1) that is independent of β-catenin was identified. This interaction is dependent upon sequences within the N-terminal region of the VDR, a domain required for VDR-DNA interactions and normal hair cycling in mice. Mutation of specific residues within the N-terminal region of the VDR not only abrogated interactions between the VDR and LEF1 but also impaired the ability of the VDR to enhance Wnt signaling in vdr(-/-) primary keratinocytes. Thus, this study demonstrates a novel interaction between the VDR and LEF1 that is mediated by the DNA-binding domain of the VDR and that is required for normal canonical Wnt signaling in keratinocytes.
维生素 D 受体（VDR）的配体非依赖性作用对于正常的形态后毛发周期是必需的；然而，VDR 发挥这些作用的分子机制尚不清楚。先前的研究表明，缺乏 VDR 的原代角质细胞中，经典 Wnt 信号通路的调节受损。为了鉴定与 VDR 相互作用的经典 Wnt 信号的关键效应物，进行了 GST 下拉研究。鉴定到 VDR 和 LEF1（淋巴增强结合因子-1）之间存在一种新的相互作用，这种相互作用不依赖于β-连环蛋白。这种相互作用依赖于 VDR N 端区域内的序列，该区域是 VDR-DNA 相互作用和小鼠正常毛发周期所必需的。VDR N 端区域内特定残基的突变不仅消除了 VDR 和 LEF1 之间的相互作用，而且还削弱了 VDR 增强 vdr(-/-)原代角质细胞中 Wnt 信号的能力。因此，这项研究表明 VDR 和 LEF1 之间存在一种新的相互作用，这种相互作用由 VDR 的 DNA 结合域介导，并且是角质细胞中正常经典 Wnt 信号所必需的。
