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Título del libro: Tgf-ß Signaling Pathway Regulation By Transcriptional Cofactors Ski And Snon In Health And Disease

Autores UNAM:
GENARO VAZQUEZ VICTORIO; DIANA GRISEL RIOS LOPEZ; ANGELES CONCEPCION TECALCO CRUZ; MARINA MACIAS SILVA;

Autores externos:

Idioma:
Inglés

Año de publicación:
2017

Palabras clave:

Cancer; Fibrosis; Ski; SMAD; Snon; TGF-ß

Resumen:

The TGF-ß (Transforming Growth Factor-beta) family plays major pleiotropic roles in the lives of metazoans, controlling key physiological processes from embryonic development to adult tissue homeostasis. Malfunctions in TGF-ß signaling lead to the development of some diseases, such as fibrosis and cancer; this reveals its role as a tumor suppressor pathway. The TGF-ß family comprises a large number of members grouped into two branches: 1) TGF-ßs, activins, inhibins, nodal, lefty, and myostatin; and 2) BMPs (Bone Morphogenetic Proteins), AMH/MIS (AntiMüllerian Hormone/Müllerian Inhibiting Substance), and GDFs (Growth and Differentiation Factors). TGF-ß signal transduction initiates after ligand binding to heteromeric Ser/Thr kinase receptors at the cell surface; the canonical pathway involves the activation of SMAD transcriptional factors through direct phosphorylation initiated by the receptors. The outcome of the TGF-signaling pathway involves the regulation of the spatial and temporal expression of >500 genes, which depends on the interaction of SMAD proteins with diverse modulators of this signaling, such as transcription factors and cofactors. In a cell context-dependent manner, TGF-ß is also able to promote cell proliferation and survival by activating noncanonical signaling pathways, such as MAPK (mitogen activated protein kinase) cascades and PI3K (phosphatidyl-inositol-3 kinase)/Akt pathways, although the molecular mechanisms involved are poorly understood. Transcriptional cofactors Ski (Sloan Kettering Institute) and SnoN (Ski novel) are SMAD interacting proteins that negatively modulate TGF-? signaling by disrupting the formation of R-SMAD/SMAD4 complexes as well as their association with p300/CBP coactivators. Ski and SnoN recruit corepressors such as N-CoR, mSin3A, and HDAC (histone deacetylases), resulting in a repression of gene transcription. In addition, Ski and SnoN proteins are also able to modulate SMAD subcellular localization. The TGF-ß/SMAD pathway and cofactors Ski and SnoN regulate each other through diverse positive and negative feedback mechanisms. These cross-regulatory processes fine-tune the TGF-ß signaling outcome. Consequently, alterations in these mutual regulatory mechanisms result in disease development, such as fibrosis and cancer. Beyond the negative regulation exerted by Ski and SnoN on TGF-ß signaling, both cofactors might possess additional functions - either as adaptor or scaffold proteins- due to their lack of catalytic activity; besides, these potential functions might be important for TGF-ß crosstalk with other signaling pathways such as nuclear receptors, GPCR (G protein coupled receptors), and Wnt and Hippo pathways, among others. The relevance of this crosstalk appears to be critical for controlling the magnitude and duration of the TGF-ß signals in every cell type that collaborates in maintaining tissue homeostasis. © 2017 by Nova Science Publishers, Inc. All rights reserved.

Entidades citadas de la UNAM:

Fuente:

ISBN:
9781536120899
Editorial:
Nova Science Publishers, Inc. Nombre de la publicación:
TGF-ß signaling pathway regulation by transcriptional cofactors ski and snon in health and disease
Página inicial:
63
Página final:
135