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.
Luo
K
K
Life Sciences Division, Lawrence Berkeley National Laboratory (LBNL), Berkeley, California 94720 USA. k_luo@ux5.lbl.gov
Stroschein
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Wang
W
W
Chen
D
D
Martens
E
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Zhou
S
S
Zhou
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Q
D002460:Cell Line; D004268:DNA-Binding Proteins / Q000378:metabolism*; D016147:Genes, Tumor Suppressor; D006801:Humans; D008233:Lymphotoxin-alpha / Q000502:physiology*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D018125:Receptors, Transforming Growth Factor beta / Q000502:physiology*; D011994:Recombinant Proteins / Q000378:metabolism; D012190:Retroviridae / Q000235:genetics; D015398:Signal Transduction; D051899:Smad2 Protein; D051900:Smad3 Protein; D051901:Smad4 Protein; D015534:Trans-Activators / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism; D014162:Transfection
D004268:DNA-Binding Proteins; D008233:Lymphotoxin-alpha; D011518:Proto-Oncogene Proteins; D018125:Receptors, Transforming Growth Factor beta; D011994:Recombinant Proteins; C497782:SMAD2 protein, human; C497790:SMAD3 protein, human; C497796:SMAD4 protein, human; D051899:Smad2 Protein; D051900:Smad3 Protein; D051901:Smad4 Protein; D015534:Trans-Activators; D014157:Transcription Factors; C060614:SKI protein, human