title: The effects of dickkopf 1 on gene expression and Wnt signaling by melanocytes: mechanisms underlying its suppression of melanocyte function and proliferation.
abstract: 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 45beta, 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 3beta 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.
authors.affiliation: Laboratory of Cell Biology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA. yujin@derma.med.osaka-u.ac.jp
authors.forename: Yuji
authors.initials: Y
authors.lastname: Yamaguchi
authors.forename: Thierry
authors.initials: T
authors.lastname: Passeron
authors.forename: Hidenori
authors.initials: H
authors.lastname: Watabe
authors.forename: Ken-ichi
authors.initials: K
authors.lastname: Yasumoto
authors.forename: Francois
authors.initials: F
authors.lastname: Rouzaud
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Hoashi
authors.forename: Vincent J
authors.initials: VJ
authors.lastname: Hearing
mesh_terms: D017209:Apoptosis / Q000235:genetics / Q000502:physiology; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology; D049109:Cell Proliferation; D002478:Cells, Cultured; D005786:Gene Expression Regulation / Q000502:physiology; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000502:physiology; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000502:physiology*; D008297:Male; D008544:Melanocytes / Q000166:cytology / Q000378:metabolism*; D051739:Microphthalmia-Associated Transcription Factor / Q000235:genetics / Q000502:physiology; D051571:Protein Kinase C-alpha / Q000235:genetics / Q000502:physiology; D012333:RNA, Messenger / Q000235:genetics / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D051153:Wnt Proteins / Q000502:physiology*; D051176:beta Catenin / Q000235:genetics / Q000502:physiology
chemical_list: C501126:DKK1 protein, human; D036341:Intercellular Signaling Peptides and Proteins; C497234:MITF protein, human; D051739:Microphthalmia-Associated Transcription Factor; D012333:RNA, Messenger; D051153:Wnt Proteins; D051176:beta Catenin; D000071679:Glycogen Synthase Kinase 3 beta; D051571:Protein Kinase C-alpha; D038362:Glycogen Synthase Kinase 3