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Regulation of scleraxis transcriptional activity by serine phosphorylation.
Bagchi, Rushita A; Wang, Ryan; Jahan, Fahmida; Wigle, Jeffrey T; Czubryt, Michael P.
Afiliação
  • Bagchi RA; St. Boniface Albrechtsen Research Centre, Winnipeg, Manitoba, Canada; Department of Physiology and Pathophysiology, University of Manitoba, Winnipeg, Manitoba, Canada.
  • Wang R; St. Boniface Albrechtsen Research Centre, Winnipeg, Manitoba, Canada; Department of Physiology and Pathophysiology, University of Manitoba, Winnipeg, Manitoba, Canada.
  • Jahan F; St. Boniface Albrechtsen Research Centre, Winnipeg, Manitoba, Canada; Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, Manitoba, Canada.
  • Wigle JT; St. Boniface Albrechtsen Research Centre, Winnipeg, Manitoba, Canada; Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, Manitoba, Canada.
  • Czubryt MP; St. Boniface Albrechtsen Research Centre, Winnipeg, Manitoba, Canada; Department of Physiology and Pathophysiology, University of Manitoba, Winnipeg, Manitoba, Canada. Electronic address: mczubryt@sbrc.ca.
J Mol Cell Cardiol ; 92: 140-8, 2016 Mar.
Article em En | MEDLINE | ID: mdl-26883788
ABSTRACT
Cardiac fibroblasts are the major extracellular matrix producing cells in the heart. Our laboratory was the first to demonstrate that the transcription factor scleraxis induces collagen 1α2 expression in both cardiac fibroblasts and myofibroblasts. Here we identify a novel post-translational mechanism by which scleraxis activity is regulated and determine its effect on transcription of genes targeted by scleraxis. Putative serine phosphorylation sites on scleraxis were revealed by in silico analysis using motif prediction software. Mutation of key serine residues to alanine, which cannot be phosphorylated, significantly attenuated the expression of fibrillar type I collagen and myofibroblast marker genes that are normally induced by scleraxis. Down-regulation of collagen 1α2 expression was due to reduced binding of the non-phosphorylated scleraxis mutant to specific E-box DNA-binding sites within the promoter as determined by chromatin immunoprecipitation in human cardiac myofibroblast cells and by electrophoretic mobility shift assay. This is the first evidence suggesting that scleraxis is phosphorylated under basal conditions. The phosphorylation sequence matched that targeted by Casein Kinase 2, and inhibition of this kinase activity disrupted the ability of scleraxis to modulate the expression of its target genes while also attenuating TGFß-induced expression of type I collagen and myofibroblast phenotype conversion marker genes. These results demonstrate a novel mechanism for regulation of scleraxis activity, which may prove to be tractable for pharmacologic manipulation.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Colágeno Tipo I / Miócitos Cardíacos / Fatores de Transcrição Hélice-Alça-Hélice Básicos / Miocárdio Tipo de estudo: Prognostic_studies Limite: Animals / Humans Idioma: En Ano de publicação: 2016 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Colágeno Tipo I / Miócitos Cardíacos / Fatores de Transcrição Hélice-Alça-Hélice Básicos / Miocárdio Tipo de estudo: Prognostic_studies Limite: Animals / Humans Idioma: En Ano de publicação: 2016 Tipo de documento: Article