Interaction of the Ski oncoprotein with Smad3 regulates TGF-beta signaling

TGF-beta treatment of cells induces a variety of physiologic responses, inc luding growth inhibition, differentiation, and induction of apoptosis. TGF- beta induces phosphorylation and nuclear translocation of Smad3. We describ e here the association of Smad3 with the nuclear protooncogene protein Ski in response to the activation of TGF-beta signaling. Association with Ski r epresses transcriptional activation by Smad3, and overexpression of Ski ren ders cells resistant to the growth-inhibitory effects of TGF-beta. The tran scriptional repression as well as the growth resistance to TGF-beta by over expression of Ski can be overcome by overexpression of Smad3. These results demonstrate that Ski is a novel component of the TGF-beta signaling pathwa y and shed light on the mechanism of action of the Ski oncoprotein.