Bikle Daniel D, Ng Dean, Oda Yuko, Hanley Karen, Feingold Kenneth, Xie Zhongjian
Department of Medicine, Veterans Affairs Medical Center and University of California, San Francisco, USA.
J Invest Dermatol. 2002 Nov;119(5):1109-13. doi: 10.1046/j.1523-1747.2002.19508.x.
Involucrin is a major protein of the cornified envelope of keratinocytes that provides much of the structural integrity of skin. Its expression is stimulated by a number of agents including calcium and 1,25-dihydroxy-vitamin D3 that promote the differentiation process in keratinocytes. Within the distal regulatory region of the involucrin promoter lies an AP-1 site and an element homologous to other vitamin D response elements. In previous studies mutation of the AP-1 site was found to reduce basal activity and block calcium stimulation of the involucrin promoter, whereas the vitamin D response element was not critical for calcium regulation. In this study both elements proved to be important for 1,25-dihydroxyvitamin D3 stimulation of the involucrin promoter. Mutation of the AP-1 site reduced basal activity and blocked 1,25-dihydroxyvitamin D3 stimulation of the involucrin promoter. In contrast, mutation of the vitamin D response element did not reduce basal expression of the involucrin promoter or prevent calcium stimulation of involucrin gene expression, but blocked 1,25-dihydroxyvitamin D3 stimulation. The vitamin D response element from the involucrin gene bound the vitamin D receptor and the retinoid X receptor, but not the retinoic acid receptor, in a specific manner. We conclude that the AP-1 site and the vitamin D response element in the involucrin promoter play important roles in mediating the action of 1,25-dihydroxyvitamin D3 on involucrin expression, but the vitamin D response element provides specificity for the 1,25-dihydroxyvitamin D3 response lacking at the AP-1 site.
兜甲蛋白是角质形成细胞角质包膜的一种主要蛋白质，它赋予皮肤大部分结构完整性。其表达受到多种因子的刺激，包括钙和1,25 - 二羟基维生素D3，这些因子促进角质形成细胞的分化过程。在兜甲蛋白启动子的远端调控区域内有一个AP - 1位点和一个与其他维生素D反应元件同源的元件。在先前的研究中，发现AP - 1位点的突变会降低基础活性并阻断钙对兜甲蛋白启动子的刺激，而维生素D反应元件对钙调节并不关键。在本研究中，这两个元件对于1,25 - 二羟基维生素D3对兜甲蛋白启动子的刺激都很重要。AP - 1位点的突变降低了基础活性并阻断了1,25 - 二羟基维生素D3对兜甲蛋白启动子的刺激。相比之下，维生素D反应元件的突变并未降低兜甲蛋白启动子的基础表达，也未阻止钙对兜甲蛋白基因表达的刺激，但阻断了1,25 - 二羟基维生素D3的刺激。兜甲蛋白基因的维生素D反应元件以特异性方式结合维生素D受体和视黄醇X受体，但不结合视黄酸受体。我们得出结论，兜甲蛋白启动子中的AP - 1位点和维生素D反应元件在介导1,25 - 二羟基维生素D3对兜甲蛋白表达的作用中起重要作用，但维生素D反应元件为AP - 1位点缺乏的1,25 - 二羟基维生素D3反应提供了特异性。
