title: Ultraviolet irradiation induces Smad7 via induction of transcription factor AP-1 in human skin fibroblasts.
abstract: Smad7 functions as an endogenous negative regulator of transforming growth factor-beta (TGF-beta)/SMAD signaling. The TGF-beta/SMAD pathway is a major regulator of collagen production in connective tissue. Reduced expression of SMAD7 has been reported in TGF-beta-mediated fibrotic diseases, characterized by overproduction of collagen. Solar ultraviolet (UV) irradiation reduces collagen production by fibroblasts in human skin in vivo. We have investigated regulation of Smad7 gene expression by UV irradiation in human skin fibroblasts. UV irradiation transiently increased SMAD7 mRNA and protein levels. Induction of SMAD7 mRNA and protein was maximal within 5 h and returned to initial basal levels 24 h post-UV irradiation. UV irradiation induced Smad7 promoter-reporter activity 3-fold. The Smad7 promoter contains functional enhancer sequences that bind transcription factors SMAD3 and activator protein-1 (AP-1). UV irradiation reduced protein binding to the Smad3 enhancer and increased binding to the AP-1 enhancer. Deletion of the AP-1 binding site in the Smad7 promoter completely abolished UV stimulation of SMAD7 transcription. Deletion of the Smad3 element had no effect on UV irradiation-induced promoter activity. UV irradiation increased mRNA and protein expression of the AP-1 family members, c-Jun and c-Fos, which bound to the AP-1 element in the Smad7 promoter. Furthermore, overexpression of dominant negative c-Jun substantially reduced UV irradiation induction of SMAD7 transcription. These data demonstrate that induction of Smad7 gene expression by UV irradiation is mediated via induction of the transcription factor AP-1 in human skin fibroblasts.
authors.affiliation: Department of Dermatology, University of Michigan Medical School, Ann Arbor, Michigan 48109-0609, USA.
authors.forename: Taihao
authors.initials: T
authors.lastname: Quan
authors.forename: Tianyuan
authors.initials: T
authors.lastname: He
authors.forename: John J
authors.initials: JJ
authors.lastname: Voorhees
authors.forename: Gary J
authors.initials: GJ
authors.lastname: Fisher
mesh_terms: D001483:Base Sequence; D001665:Binding Sites; D015152:Blotting, Northern; D015153:Blotting, Western; D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism*; D017353:Gene Deletion; D005786:Gene Expression Regulation; D005799:Genes, Dominant; D017930:Genes, Reporter; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008156:Luciferases / Q000378:metabolism; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D012313:RNA / Q000737:chemistry; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012867:Skin / Q000378:metabolism*; D051906:Smad7 Protein; D013997:Time Factors; D015534:Trans-Activators / Q000378:metabolism*; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000378:metabolism; D014466:Ultraviolet Rays
chemical_list: D004268:DNA-Binding Proteins; D016760:Proto-Oncogene Proteins c-fos; D012333:RNA, Messenger; C497806:SMAD7 protein, human; D051906:Smad7 Protein; D015534:Trans-Activators; D018808:Transcription Factor AP-1; D016212:Transforming Growth Factor beta; D012313:RNA; D003094:Collagen; D008156:Luciferases; D048031:JNK Mitogen-Activated Protein Kinases