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Vol. 13, No. 17, pp. 2196-2206, September 1, 1999
signaling
1 Life Sciences Division, Smad proteins are critical signal transducers downstream of the
receptors of the transforming growth factor- [Key Words:
Ski; TGF
(TGF) superfamily. On phosphorylation and activation by the active TGF 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-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-responsive cell line renders it resistant to
TGF-induced growth inhibition and defective in activation of JunB
expression. This ability to overcome TGF-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.
; Smad proteins; growth
inhibition; signal transduction; transcriptional activation]
GENES & DEVELOPMENT 13:2196-2206 © 1999 by Cold Spring Harbor Laboratory Press ISSN 0890-9369/99 $5.00
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