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Scleraxis works synergistically with Smads to regulate collagen gene expression
Author(s) -
Bagchi Rushita,
Czubryt Michael
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.26.1_supplement.1059.2
Subject(s) - transactivation , microbiology and biotechnology , luciferase , gene expression , smad , promoter , chemistry , transcription factor , gene , biology , reporter gene , signal transduction , biochemistry , transfection
Elevated type I collagen expression in cardiac fibrosis impairs heart function. We have shown that the transcription factor scleraxis (Scx) is expressed by cardiac fibroblasts and myofibroblasts, and is sufficient to regulate human collagen Iα2 ( COLIα2 ) expression. Here we studied the interaction of Scx with the fibrotic Smad signaling pathway. We identified Scx binding sites (E‐boxes) within the COLIα2 proximal gene promoter, examined promoter occupancy by Scx using ChIP assay, and measured promoter activation by Scx and/or Smads via luciferase gene reporter assays. Scx augmented TGF‐β 1 transactivation of the promoter. Scx and Smad3 synergistically up‐regulated COLIα2 promoter transactivation. Mutation of the promoter Smad binding element significantly reduced transactivation by Scx. A similar effect of E‐box mutations on Smad3‐mediated activation was also observed, suggesting that cross‐talk in these pathways is required for maximal gene activity. Scx expression was up‐regulated by Smad3 and down‐regulated by Smad7, further supporting cross‐pathway signaling. A dominant negative Scx mutant completely abrogated COLIα2 gene expression by TGF‐β 1 . Our results indicate that Scx and Smads synergistically co‐regulate collagen gene expression, and that interference with this interaction may represent a novel avenue for anti‐fibrotic therapy development. Supported by CIHR and MHRC.