title: UV irradiation induces Snail expression by AP-1 dependent mechanism in human skin keratinocytes.
abstract: BACKGROUND
  Ultraviolet (UV) irradiation from the sun is the major cause of keratinocyte skin cancer. Transcription factor Snail plays an important role in epithelial-to-mesenchymal transition and epithelial tumor formation.
  
  
  OBJECTIVE
  The aims of this study are to determine the regulation of Snail expression of ultraviolet (UV) irradiation on Snail expression in human skin in vivo, and the mechanisms by which UV irradiation induces Snail expression, in human keratinocytes.
  
  
  METHODS
  Real-time RT-PCR was employed to measure Snail expression in human skin in vivo and cultured human keratinocytes. Luciferase assay and electrophoretic mobility shift assay (EMSA) were employed to investigate transcriptional regulation of the in Snail gene promoter.
  
  
  RESULTS
  Ultraviolet (UV) irradiation transiently induces Snail expression in human skin in vivo and cultured human keratinocytes. Snail induction is significantly reduced by specific inhibitors of ERK, p38 or JNK, indicating each of the three major mitogen-activated protein kinase (MAPK) pathways participate in Snail regulation. AP-1 transcription factor complex, a downstream target of MAPK signaling, is required for Snail induction. Inhibition of AP-1 activity by over-expression of dominant-negative c-Jun substantially reduces Snail induction. Analyses of the Snail promoter, revealed the presence of an AP-1 binding site. EMSA assay demonstrated that UV irradiation specifically induced c-Jun binding to this AP-1 site. Mutation of the AP-1-binding site completely blocked protein binding and inhibited UV irradiation-induced Snail promoter activity.
  
  
  CONCLUSIONS
  UV irradiation induces Snail gene expression in human skin keratinocytes. This induction is mediated by MAPK-AP-1 dependent signaling pathway. Elevated expression of Snail in response to chronic UV irradiation in human skin may contribute to UV irradiation-induced skin tumor development.
authors.affiliation: Department of Dermatology, University of Michigan, Ann Arbor, MI 48109-5609, USA.
authors.forename: Yong
authors.initials: Y
authors.lastname: Li
authors.forename: Ying
authors.initials: Y
authors.lastname: Liu
authors.forename: Yiru
authors.initials: Y
authors.lastname: Xu
authors.forename: John J
authors.initials: JJ
authors.lastname: Voorhees
authors.forename: Gary J
authors.initials: GJ
authors.lastname: Fisher
mesh_terms: D002478:Cells, Cultured / Q000378:metabolism; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics / Q000528:radiation effects; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000235:genetics / Q000528:radiation effects; D006801:Humans; D015603:Keratinocytes / Q000378:metabolism* / Q000502:physiology / Q000528:radiation effects*; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D012867:Skin / Q000378:metabolism* / Q000528:radiation effects*; D012879:Skin Physiological Phenomena / Q000235:genetics / Q000528:radiation effects; D000071250:Snail Family Transcription Factors; D018808:Transcription Factor AP-1 / Q000502:physiology; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism / Q000528:radiation effects*; D014466:Ultraviolet Rays; D015854:Up-Regulation / Q000235:genetics
chemical_list: D016755:Proto-Oncogene Proteins c-jun; D000071250:Snail Family Transcription Factors; D018808:Transcription Factor AP-1; D014157:Transcription Factors; D020928:Mitogen-Activated Protein Kinases