The Ski oncoprotein interacts with the Smad proteins to repress TGF beta signaling

Smad proteins are critical signal transducers downstream of the receptors o f the transforming growth factor-beta (TGF beta) superfamily. On phosphoryl ation and activation by the active TGF beta receptor complex, Smad2 and Sma d3 form hetero-oligomers with Smad4 and translocate into the nucleus, where they interact with different cellular partners, bind to DNA, regulate tran scription of various downstream response genes, and cross-talk with other s ignaling pathways. Here we show that a nuclear oncoprotein, Ski, can intera ct directly with Smad2, Smad3, and Smad4 on a TGF beta-responsive promoter element and repress their abilities to activate transcription through recru itment of the nuclear transcriptional corepressor N-CoR and possibly its as sociated histone deacetylase complex. Overexpression of Ski in a TGF beta-r esponsive cell Line renders it resistant to TGF beta-induced growth inhibit ion and defective in activation of JunB expression. This ability to overcom e TGF beta-induced growth arrest may be responsible for the transforming ac tivity of Ski in human and avian canter cells. Our studies suggest a new pa radigm for inactivation of the Smad proteins by an oncoprotein through tran scriptional repression.