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In addition to its action in cellular transformation, the Ski proto-oncogene has dramatic effects on cell death and differentiation during development. Ski functions as a potent anti-apoptotic protein by binding to the pro-apoptotic protein, Smac. Smac binds two separate domains of the apoptosis inhibitor XIAP, preventing their inhibition of caspase-3 and caspase-9. Ski blocks the interaction between Smac and XIAP, and overcomes Smac’s dual inhibitory effects on XIAP both in vitro and in vivo. Upon induction of apoptosis, the intracellular distribution of Ski changes from exclusively nuclear to partially cytoplasmic, facilitating its interaction with active Smac. Ski also interacts with XIAP, up regulates the expression of anti-apoptotic Bcl2 family members, Ku70 and the anti-apoptotic, secretary form of Clusterin, while it down regulates the proapoptotic nuclear form of Clusterin. These findings identify a novel activity of the Ski protein that should play an important role in its functions during development and oncogenesis. Ski encodes a co-factor that can either repress or activate transcription, depending on its protein partners. These studies focused on Ski’s transcriptional repression activity and found that Ski achieves its inhibitory effect via multiple mechanisms, in which histone deacetylases and heterochromatin protein 1á are involved. Over expressed Ski co-fractionates together with phosphorylated Smad2 in a 1.0 MDa complex. Even though the interaction with Smads is important for Ski to repress the TGFâ pathway, too strong binding of Smads reduces Ski’s inhibitory effect.