Transcriptional cofactors Ski and SnoN are major regulatorsof the TGF-β/Smad signaling pathway in health and disease

The transforming growth factor-β(TGF-β)family plays major pleiotropic roles by regulating many physiological processes in development and tissue homeostasis.The TGF-βsignaling pathway outcome relies on the control of the spatial and temporal expression of>500 genes,which depend on the functions of the Smad protein along with those of diverse modulators of this signaling pathway,such as transcriptional factors and cofactors.Ski(Sloan-Kettering Institute)and SnoN(Ski novel)are Smadinteracting proteins that negatively regulate the TGF-βsignaling pathway by disrupting the formation of R-Smad/Smad4 complexes,as well as by inhibiting Smad association with the p300/CBP coactivators.The Ski and SnoN transcriptional cofactors recruit diverse corepressors and histone deacetylases to repress gene transcription.The TGF-β/Smad pathway and coregulators Ski and SnoN clearly regulate each other through several positive and negative feedback mechanisms.Thus,these cross-regulatory processes finely modify the TGF-βsignaling outcome as they control the magnitude and duration of the TGF-βsignals.As a result,any alteration in these regulatory mechanisms may lead to disease development.Therefore,the design of targeted therapies to exert tight control of the levels of negative modulators of the TGF-βpathway,such as Ski and SnoN,is critical to restore cell homeostasis under the specific pathological conditions in which these cofactors are deregulated,such as fibrosis and cancer.