Transcriptional profiling of keratinocytes reveals a vitamin D-regulated epidermal differentiation network
Transcriptional profiling of keratinocytes reveals a vitamin D-regulated epidermal differentiation network
复制标题
DOI：
10.1111/j.0022-202x.2005.23641.x
复制
发表时间：
2005-04-01
影响因子：
6.5
通讯作者：
Nagpal, S
中科院分区：
文献类型：
--
作者：
Lu, JF;Goldstein, KM;Nagpal, S
1 α，25-二羟基维生素D-3 [1,25(OH)(2)D-3]调节矿物质稳态，并表现出有效的抗增殖、促分化和免疫调节活性。它通过与维生素D受体（VDR）结合介导这些作用，维生素D受体属于类固醇/甲状腺激素核受体超家族。由于角化细胞分化和抗增殖活性，1,25(OH)(2)D-3及其合成类似物在银屑病治疗中有效，并有望治疗光化性角化病和鳞状细胞癌。为了阐明角化细胞中的VDR信号通路，我们使用寡核苷酸微阵列检测了1,25(OH)(2)D-3处理后的基因表达谱。在研究的12600个基因中，82个基因上调，16个基因下调，其中许多基因与分化、增殖和免疫反应有关。我们已经确定了三个维生素d应答染色体位点（1p36, 19q13和6p25），并显示了对1,25(OH)(2)D-3的响应诱导了各种II类肿瘤抑制/生长调节基因。最后，基因表达的定量差异揭示了维生素d调控的分化网络，并鉴定出肽精氨酸脱亚胺酶、钾化酶、丝氨酸蛋白酶抑制剂家族成员、kruppel样因子4和c-fos是维生素d应答基因，其蛋白产物可能在正常和病变状态下表皮分化中发挥重要作用。
1 alpha,25-dihydroxyvitamin D-3 [1,25(OH)(2)D-3] regulates mineral homeostasis and exhibits potent anti-proliferative, prodifferentiative, and immunomodulatory activities. It mediates these effects by binding to the vitamin D receptor (VDR), which belongs to the superfamily of steroid/thyroid hormone nuclear receptors. As a result of keratinocyte differentiation and anti-proliferation activities, 1,25(OH)(2)D-3 and its synthetic analogs are therapeutically effective in psoriasis and show promise for the treatment of actinic keratosis and squamous cell carcinoma. To elucidate the VDR signaling pathway in keratinocytes, we examined the gene expression profile with 1,25(OH)(2)D-3 treatment using oligonucleotide microarrays. Out of the 12,600 genes investigated, 82 were upregulated and 16 were downregulated and many of these were involved in differentiation, proliferation, and immune response. We have identified three vitamin D-responsive chromosomal loci (1p36, 19q13, and 6p25) and show the induction of various class II tumor suppressor/growth-regulatory genes in response to 1,25(OH)(2)D-3. Finally, quantitative differences in gene expression revealed a vitamin D-regulated differentiation network and identified peptidylarginine deiminases, kallikreins, serine proteinase inhibitor family members, Kruppel-like factor 4, and c-fos as vitamin D-responsive genes, whose protein products may play an important role in epidermal differentiation in normal and diseased state.