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

Abstract

The transforming growth factor-β (TGF-β) family plays major pleiotropic roles by regulating many physiological processes in development and tissue homeostasis. The TGF-β signaling 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 Smad-interacting proteins that negatively regulate the TGF-β signaling 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-β signaling outcome as they control the magnitude and duration of the TGF-β signals. 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-β pathway, 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.

Ski drives an acute increase in MMP-9 gene expression and release in primary cardiac myofibroblasts

“…While Ski effectively sequesters and binds Smads, which are needed for the canonical response to TGF‐ β 1 , the mechanisms by which Ski modulates these functions may extend beyond its role as an endogenous repressor of TGF‐ β 1 (Tecalco‐Cruz et al. ). We have shown that TGF‐ β 1 itself leads to activation and movement of Ski to the nucleus (bound to R‐Smads) in MFB (Cunnington et al., ).…”

“…To effect this specific response in combination with decreased MFB marker proteins and adhesion proteins ( FAK and paxillin) Ski may serve as a scaffold for number of cofactors including Smads (Tecalco‐Cruz et al. ). On the other hand, in chronic cardiac injury (infarcted hearts) we have found that the intracellular distribution of Ski is shifted to the cytosol (Cunnington et al.…”

“…We hypothesize that Ski exerts its anti-fibrotic effects, in part, by causing enhanced release of MMP-9 in acutely stimulated cardiac fibroblasts and in cardiac myofibroblasts. To effect this specific response in combination with decreased MFB marker proteins and adhesion proteins (FAK and paxillin) Ski may serve as a scaffold for number of cofactors including Smads (Tecalco-Cruz et al 2018). On the other hand, in chronic cardiac injury (infarcted hearts) we have found that the intracellular distribution of Ski is shifted to the cytosol (Cunnington et al 2011 associated with preservation of normal matrix distribution when compared to reduced expression observed in human patients with overt cardiac fibrosis (Sakamuri et al 2016).…”

“…Ski is a known repressor of the TGF‐ β 1 signaling pathway that disrupts R‐Smad/Smad4 complex signaling (Tecalco‐Cruz et al. ) in various cell types (Akiyoshi et al. ; Prunier et al.…”

“…In this context, R-Smad activation by TGF-b 1 is a key driver of myofibroblast-mediated cardiac fibrosis and activation of CF (Leask 2010). Ski is a known repressor of the TGF-b 1 signaling pathway that disrupts R-Smad/Smad4 complex signaling (Tecalco-Cruz et al 2018) in various cell types (Akiyoshi et al 1999;Prunier et al 2003;Ueki and Hayman 2003;Ferrand et al 2010). We have noted that Ski rapidly translocates from the cytosol to the nucleus after treatment of MFB with TGF-b 1 (Cunnington et al 2011).…”