Smad proteins mediate transforming growth factor-β (TGF-β) signaling to regulate cell growth and differentiation. The SnoN oncoprotein was found to interact with Smad2 and Smad4 and to repress their abilities to activate transcription through recruitment of the transcriptional corepressor N-CoR. Immediately after TGF-β stimulation, SnoN is rapidly degraded by the nuclear accumulation of Smad3, allowing the activation of TGF-β target genes. By 2 hours, TGF-β induces a marked increase in SnoN expression, resulting in termination of Smad-mediated transactivation. Thus, SnoN maintains the repressed state of TGF-β-responsive genes in the absence of ligand and participates in negative feedback regulation of TGF-β signaling.