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

Kunxin Luo; Shannon L. Stroschein; Wei Wang; Dan Chen; Eric Martens; Sharleen Zhou; Qiang Zhou

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

Life Sciences Division, Lawrence Berkeley National Laboratory (LBNL), and Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, California 94720 USA; Department of Biology, University of Science and Technology of China, Hefei, Anhui, China

Abstract

Smad proteins are critical signal transducers downstream of the receptors of the transforming growth factor-β (TGFβ) superfamily. On phosphorylation and activation by the active TGFβ 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 TGFβ-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 TGFβ-responsive cell line renders it resistant to TGFβ-induced growth inhibition and defective in activation of JunB expression. This ability to overcome TGFβ-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.

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