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Constitutive activation of c‐Abl/protein kinase C‐δ/Fli1 pathway in dermal fibroblasts derived from patients with localized scleroderma
Author(s) -
Noda S.,
Asano Y.,
Akamata K.,
Aozasa N.,
Taniguchi T.,
Takahashi T.,
Ichimura Y.,
Toyama T.,
Sumida H.,
Yanaba K.,
Tada Y.,
Sugaya M.,
Kadono T.,
Sato S.
Publication year - 2012
Publication title -
british journal of dermatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.304
H-Index - 179
eISSN - 1365-2133
pISSN - 0007-0963
DOI - 10.1111/j.1365-2133.2012.11055.x
Subject(s) - fli1 , microbiology and biotechnology , protein kinase c , abl , gene silencing , signal transduction , biology , cancer research , chemistry , tyrosine kinase , chromosomal translocation , gene , biochemistry
Summary 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. Objectives 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.