Signal-dependent N-CoR requirement for repression by the Ski oncoprotein

The oncoprotein Ski represses transforming growth factor-beta (TGF-beta) and nuclear receptor signaling. To achieve this, Ski has been proposed to recruit the corepressor N-CoR to either the TGF-beta-regulated Smad transcription factors or nuclear receptors. Here we define the role of the Ski/N-CoR interaction in Ski-mediated repression of TGF-beta and vitamin D signaling. We show that Ski can negatively regulate vitamin D-mediated transcription by directly interacting with the vitamin D receptor. More importantly, a Ski single point mutant lacking N-CoR binding revealed that the Ski/N-CoR interaction is essential for repression of vitamin D signaling, but, surprisingly, not TGF-beta signaling. Thus, Ski modulates transcription in either an N-CoR-dependent or -independent manner depending on the signaling pathways targeted.