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

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.
Mesh Terms:
Cell Line, DNA-Binding Proteins, Genes, Tumor Suppressor, Humans, Lymphotoxin-alpha, Proto-Oncogene Proteins, Receptors, Transforming Growth Factor beta, Recombinant Proteins, Retroviridae, Signal Transduction, Smad2 Protein, Smad3 Protein, Smad4 Protein, Trans-Activators, Transcription Factors, Transfection
Genes Dev.
Date: Sep. 01, 1999
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