The Ski oncoprotein interacts with the Smad proteins to repress TGFbeta signaling

Genes Dev. 1999 Sep 1;13(17):2196-206. doi: 10.1101/gad.13.17.2196.

Abstract

Smad proteins are critical signal transducers downstream of the receptors of the transforming growth factor-beta (TGFbeta) superfamily. On phosphorylation and activation by the active TGFbeta receptor complex, Smad2 and Smad3 form hetero-oligomers with Smad4 and translocate into the nucleus, where they interact with different cellular partners, bind to DNA, regulate transcription of various downstream response genes, and cross-talk with other signaling pathways. Here we show that a nuclear oncoprotein, Ski, can interact directly with Smad2, Smad3, and Smad4 on a TGFbeta-responsive promoter element and repress their abilities to activate transcription through recruitment of the nuclear transcriptional corepressor N-CoR and possibly its associated histone deacetylase complex. Overexpression of Ski in a TGFbeta-responsive cell line renders it resistant to TGFbeta-induced growth inhibition and defective in activation of JunB expression. This ability to overcome TGFbeta-induced growth arrest may be responsible for the transforming activity of Ski in human and avian cancer cells. Our studies suggest a new paradigm for inactivation of the Smad proteins by an oncoprotein through transcriptional repression.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Cell Line
  • DNA-Binding Proteins / metabolism*
  • Genes, Tumor Suppressor
  • Humans
  • Lymphotoxin-alpha / physiology*
  • Proto-Oncogene Proteins / metabolism*
  • Receptors, Transforming Growth Factor beta / physiology*
  • Recombinant Proteins / metabolism
  • Retroviridae / genetics
  • Signal Transduction
  • Smad2 Protein
  • Smad3 Protein
  • Smad4 Protein
  • Trans-Activators / metabolism*
  • Transcription Factors / metabolism
  • Transfection

Substances

  • DNA-Binding Proteins
  • Lymphotoxin-alpha
  • Proto-Oncogene Proteins
  • Receptors, Transforming Growth Factor beta
  • Recombinant Proteins
  • SMAD2 protein, human
  • SMAD3 protein, human
  • SMAD4 protein, human
  • Smad2 Protein
  • Smad3 Protein
  • Smad4 Protein
  • Trans-Activators
  • Transcription Factors
  • SKI protein, human