The effects of dickkopf 1 on gene expression and Wnt signaling by melanocytes: Mechanisms underlying its suppression of melanocyte function and proliferation
The effects of dickkopf 1 on gene expression and Wnt signaling by melanocytes: Mechanisms underlying its suppression of melanocyte function and proliferation
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DOI：
10.1038/sj.jid.5700629
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发表时间：
2007-05-01
影响因子：
6.5
通讯作者：
Hearing, Vincent J.
中科院分区：
文献类型：
--
作者：
Yamaguchi, Yuji;Passeron, Thierry;Hearing, Vincent J.
Dickkopf 1（DKK 1）通过抑制β-连环蛋白和小眼症相关转录因子（MITF），以高mRNA水平由手掌和脚掌上的人皮肤真皮中的成纤维细胞表达，抑制这些区域的表皮中的黑素细胞的功能和增殖。在这项研究中，我们研究了DKK 1的蛋白表达水平之间的掌跖和非掌跖地区和DKK 1黑素细胞基因表达谱和Wnt信号通路的影响，使用DNA微阵列技术，逆转录酶-PCR，蛋白质印迹，三维重建皮肤，免疫细胞化学和免疫组织化学。DKK 1应答基因包括编码参与调节黑素细胞发育、生长、分化和凋亡的蛋白质的基因（包括Kremen 1、G偶联受体51、脂蛋白受体相关蛋白6、低密度脂蛋白受体、肿瘤坏死因子受体超家族10、生长停滞和DNA损伤诱导基因45 β和MITF）。特别令人感兴趣的是在用DKK 1处理的黑素细胞中MITF表达的快速降低，这与通过Ser 9磷酸化的β-连环蛋白和葡萄糖合成酶激酶3 β的活性降低以及蛋白激酶C α的表达上调同时发生。这些结果进一步阐明了DKK 1抑制黑素细胞密度和分化的机制，并有助于解释为什么富含DKK 1的掌跖表皮通过间充质-上皮相互作用比非掌跖表皮更苍白。
Dickkopf 1 (DKK1), which is expressed at high mRNA levels by fibroblasts in the dermis of human skin on the palms and soles, inhibits the function and proliferation of melanocytes in the epidermis of those areas via the suppression of beta-catenin and microphthalmia-associated transcription factor (MITF). In this study, we investigated the protein expression levels of DKK1 between palmoplantar and non-palmoplantar areas and the effects of DKK1 on melanocyte gene expression profiles and on Wnt signaling pathways using DNA microarray technology, reverse transcriptase-PCR, Western blot, 3-dimensional reconstructed skin, immunocytochemistry, and immunohistochemistry. DKK1-responsive genes included those encoding proteins involved in the regulation of melanocyte development, growth, differentiation, and apoptosis (including Kremen 1, G-coupled receptor 51, lipoprotein receptor-related protein 6, low-density lipoprotein receptor, tumor necrosis factor receptor super-family 10, growth arrest and DNA-damage- inducible gene 45 beta, and MITF). Of special interest was the rapid decrease in expression of MITF in melanocytes treated with DKK1, which is concurrent with the decreased activities of beta-catenin and of glucose-synthase kinase 3 beta via phosphorylation at Ser9 and with the upregulated expression of protein kinase C alpha. These results further clarify the mechanism by which DKK1 suppresses melanocyte density and differentiation, and help explain why DKK1-rich palmoplantar epidermis is paler than non-palmoplantar epidermis via mesenchymal-epithelial interactions.