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

Smad proteins are critical signal transducers downstream of the receptors of the transforming growth factor-beta (TGF beta) superfamily. On phosphorylation and activation by the active TGF beta 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 TGF beta-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 TGF beta-responsive cell Line renders it resistant to TGF beta-induced growth inhibition and defective in activation of JunB expression. This ability to overcome TGF beta-induced growth arrest may be responsible for the transforming activity of Ski in human and avian canter cells. Our studies suggest a new paradigm for inactivation of the Smad proteins by an oncoprotein through transcriptional repression.