TGFbeta1 regulation of vimentin gene expression during differentiation of the C2C12 skeletal myogenic cell line requires Smads, AP-1 and Sp1 family members

Biochim Biophys Acta. 2007 Mar;1773(3):427-39. doi: 10.1016/j.bbamcr.2006.11.017. Epub 2006 Dec 6.


Vimentin exhibits a complex pattern of developmental and tissue-specific expression regulated by such growth factors as TGFbeta1, PDGF, FGF, EGF and cytokines. Vimentin is expressed in the more migratory, mesenchymal cell and its expression is often down-regulated to make way for tissue-specific intermediate filaments proteins such as desmin in muscle. Here, we suggest a mechanism to explain how TGFbeta1 contributes to the up-regulation of vimentin expression while blocking myogenesis. TGFbeta1 binds to serine/threonine kinase receptors resulting in the phosphorylation of Smad2 and Smad3, followed by formation of a heteromeric complex with Smad4. The translocation of this complex to the nucleus modulates transcription of selected genes such as vimentin. However, the vimentin gene lacks a consensus TGFbeta1 response element. By transient transfection analysis of vimentin's various promoter elements fused to the CAT reporter gene, we have determined that tandem AP-1 sites surrounded by GC-boxes are required for TGFbeta1 induction. Mutations within this region eliminated the ability of Smad3 to induce reporter gene expression. DNA precipitation and ChIP assays suggest that c-Jun, c-Fos, Smad3 and Sp1/Sp3 interact over this region, but this interaction changes during myogenesis with TGFbeta1 induction.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Base Sequence
  • Cell Differentiation
  • Cell Line
  • Gene Expression Regulation / drug effects
  • Genes, Reporter / genetics
  • JNK Mitogen-Activated Protein Kinases / metabolism
  • Mice
  • Molecular Sequence Data
  • Myoblasts, Skeletal / cytology*
  • Myoblasts, Skeletal / drug effects
  • Myoblasts, Skeletal / metabolism*
  • Protein Binding
  • Proto-Oncogene Proteins c-fos / metabolism
  • Smad Proteins / classification
  • Smad Proteins / metabolism*
  • Sp1 Transcription Factor / metabolism*
  • Transcription Factor AP-1 / metabolism*
  • Transforming Growth Factor beta1 / pharmacology*
  • Vimentin / genetics*
  • p300-CBP Transcription Factors / metabolism


  • Proto-Oncogene Proteins c-fos
  • Smad Proteins
  • Sp1 Transcription Factor
  • Transcription Factor AP-1
  • Transforming Growth Factor beta1
  • Vimentin
  • p300-CBP Transcription Factors
  • JNK Mitogen-Activated Protein Kinases