title: Constitutive activation of c-Abl/protein kinase C-δ/Fli1 pathway in dermal fibroblasts derived from patients with localized scleroderma.
abstract: BACKGROUND
  A noncanonical pathway of transforming growth factor-β signalling, the c-Abl/protein kinase C-δ (PKC-δ)/Friend leukemia virus integration 1 (Fli1) axis, is a powerful regulator of collagen synthesis in dermal fibroblasts.
  
  
  OBJECTIVE
  To investigate the significance of the c-Abl/PKC-δ/Fli1 pathway for the establishment of the profibrotic phenotype in lesional dermal fibroblasts from patients with localized scleroderma (LSc).
  
  
  METHODS
  The activation status of the c-Abl/PKC-δ/Fli1 pathway was evaluated by immunoblotting and chromatin immunoprecipitation using cultured dermal fibroblasts from patients with LSc and closely matched healthy controls and by immunostaining on skin sections. The effects of a platelet-derived growth factor receptor inhibitor AG1296 and gene silencing of c-Abl on the expression levels of type I collagen were evaluated by immunoblotting.
  
  
  RESULTS
  The phosphorylation levels of Fli1 at threonine 312 were increased, while the total Fli1 levels and the binding of Fli1 to the COL1A2 promoter were decreased, in cultured LSc fibroblasts compared with cultured normal fibroblasts. Furthermore, in cultured LSc fibroblasts, the expression levels of c-Abl were elevated compared with cultured normal fibroblasts and PKC-δ was preferentially localized in the nucleus. These findings were also confirmed in vivo by immunohistochemistry using skin sections. Moreover, gene silencing of c-Abl, but not AG1296, significantly suppressed the expression of type I collagen in cultured LSc fibroblasts.
  
  
  CONCLUSIONS
  Constitutive activation of the c-Abl/PKC-δ/Fli1 pathway at least partially contributes to the establishment of the profibrotic phenotype in LSc dermal fibroblasts, which provides a novel molecular basis to explain the efficacy of imatinib against skin sclerosis in a certain subset of LSc.
authors.affiliation: Department of Dermatology, University of Tokyo Graduate School of Medicine, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Noda
authors.forename: Y
authors.initials: Y
authors.lastname: Asano
authors.forename: K
authors.initials: K
authors.lastname: Akamata
authors.forename: N
authors.initials: N
authors.lastname: Aozasa
authors.forename: T
authors.initials: T
authors.lastname: Taniguchi
authors.forename: T
authors.initials: T
authors.lastname: Takahashi
authors.forename: Y
authors.initials: Y
authors.lastname: Ichimura
authors.forename: T
authors.initials: T
authors.lastname: Toyama
authors.forename: H
authors.initials: H
authors.lastname: Sumida
authors.forename: K
authors.initials: K
authors.lastname: Yanaba
authors.forename: Y
authors.initials: Y
authors.lastname: Tada
authors.forename: M
authors.initials: M
authors.lastname: Sugaya
authors.forename: T
authors.initials: T
authors.lastname: Kadono
authors.forename: S
authors.initials: S
authors.lastname: Sato
mesh_terms: D000293:Adolescent; D000328:Adult; D001549:Benzamides; D016022:Case-Control Studies; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D000068877:Imatinib Mesylate; D008297:Male; D008875:Middle Aged; D010766:Phosphorylation; D010879:Piperazines / Q000494:pharmacology; D051745:Protein Kinase C-delta / Q000235:genetics / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051789:Proto-Oncogene Protein c-fli-1 / Q000235:genetics / Q000378:metabolism*; D016315:Proto-Oncogene Proteins c-abl / Q000378:metabolism*; D011743:Pyrimidines / Q000494:pharmacology; D012594:Scleroderma, Localized / Q000235:genetics / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000187:drug effects / Q000235:genetics / Q000378:metabolism
chemical_list: D001549:Benzamides; C078433:FLI1 protein, human; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D051789:Proto-Oncogene Protein c-fli-1; D011743:Pyrimidines; D016212:Transforming Growth Factor beta; D000068877:Imatinib Mesylate; D016315:Proto-Oncogene Proteins c-abl; D051745:Protein Kinase C-delta