Journal
SIGNAL TRANSDUCTION AND TARGETED THERAPY
Volume 3, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41392-018-0015-8
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Funding
- CONACYT [240224]
- PAPIIT/DGAPA/UNAM [IN208115, IN208118, IA200916]
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The transforming growth factor-beta (TGF-beta) family plays major pleiotropic roles by regulating many physiological processes in development and tissue homeostasis. The TGF-beta 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 Smadinteracting proteins that negatively regulate the TGF-beta 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-beta/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-beta signaling outcome as they control the magnitude and duration of the TGF-beta 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-beta 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.
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