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Transgelin is a direct target of TGF-beta/Smad3-dependent epithelial cell migration in lung fibrosis.

Abstract
Enhanced transforming growth factor (TGF) -beta signaling contributes to idiopathic pulmonary fibrosis (IPF), a progressive and fatal disease characterized by alveolar epithelial type II (ATII) cell hyperplasia, (myo)fibroblast accumulation, and excessive extracellular matrix deposition. TGF-beta is a potent inducer of lung fibrosis, and it regulates the ATII cell phenotype; however, direct TGF-beta target genes controlling the ATII cell phenotype remain elusive. Here, we identified the transgelin (tagln) gene as a novel immediate target of TGF-beta/Smad3-dependent gene expression in ATII cells using a Smad3 chromatin immunoprecipitation (ChIP) screen. Direct ChIP confirmed the rapid and specific binding of Smad3 to the tagln promoter. Luciferase assays demonstrated transactivation of the tagln promoter by activin-like kinase (Alk) 5-mediated TGF-beta signaling. TGF-beta treatment resulted in rapid up-regulation of tagln, but not tagln2, mRNA and protein expression, assessed by reverse transcription-polymerase chain reaction (RT-PCR), Western blotting, and immunofluorescence. In vivo, tagln expression was significantly increased in ATII cells of mice during bleomycin-induced lung fibrosis, as well as in lung specimen obtained from IPF patients, as assessed by RT-PCR and immunohistochemistry. Knockdown of tagln using siRNA inhibited TGF-beta-induced migration of lung epithelial A549 cells, as well as primary ATII cells. We thus identified tagln as a novel target of TGF-beta/Smad3-dependent gene expression in ATII cells. Increased ATII cell expression of tagln in experimental and idiopathic pulmonary fibrosis may contribute to TGF-beta-dependent ATII cell injury, repair, and migration in lung fibrosis.
AuthorsHaiying Yu, Melanie Königshoff, Aparna Jayachandran, Dan Handley, Werner Seeger, Naftali Kaminski, Oliver Eickelberg
JournalFASEB journal : official publication of the Federation of American Societies for Experimental Biology (FASEB J) Vol. 22 Issue 6 Pg. 1778-89 (Jun 2008) ISSN: 1530-6860 [Electronic] United States
PMID18245174 (Publication Type: Journal Article)
Chemical References
  • Microfilament Proteins
  • Muscle Proteins
  • Receptors, Transforming Growth Factor beta
  • Smad3 Protein
  • Transforming Growth Factor beta
  • transgelin
Topics
  • Cell Line
  • Cell Movement
  • Epithelial Cells (pathology)
  • Humans
  • Microfilament Proteins (drug effects, genetics)
  • Muscle Proteins (drug effects, genetics)
  • Promoter Regions, Genetic
  • Pulmonary Fibrosis (pathology)
  • Receptors, Transforming Growth Factor beta
  • Smad3 Protein (metabolism)
  • Transforming Growth Factor beta (pharmacology)

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