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Terpenoids: The Biological Key Molecules
Published in Dijendra Nath Roy, Terpenoids Against Human Diseases, 2019
Moumita Majumdar, Dijendra Nath Roy
The transforming growth factor β (TGF-β) superfamily comprises numerous growth factors—including, for example, TGF-β-1,2,3 and bone morphogenetic proteins—by which they regulate physiological processes such as cell differentiation, development, proliferation, adhesion, movement and, ultimately, programmed cell death. Cytokines of the TGF-β superfamily accelerate heterotetrameric receptor complex formation. These structures are composed of mainly two transmembrane receptor proteins, namely TGF-β receptor I (TβRI) and TGF-β receptor II (TβRII). Phosphorylation of these receptors results in the activation of a downstream transcription factor, which in turn phosphorylates SMAD2 and SMAD3. TGF-β receptor 1 phosphorylates R-SMADs on their C terminus through the intracellular kinase domain, leading to R-SMAD activation (Wharton and Derynck 2009). Then, R-SMADs interact with SMAD4 to form a SMAD complex, leading to its translocation to the nucleus for gene expression. On the other hand, bone morphogenetic proteins activate SMADl, SMAD5 and SMAD8.
Mechanobiology of Heart Valves
Published in Jiro Nagatomi, Eno Essien Ebong, Mechanobiology Handbook, 2018
Joshua D. Hutcheson, Michael P. Nilo, W. David Merryman
The detailed cellular signaling pathways associated with AVIC myofibroblast activation are poorly understood; however, TGF-β1 activation and receptor binding has been identified as a major contributor to myofibroblast activation.68–70 TGF-β1 is a member of the transforming growth factor superfamily of cytokines. TGF-β1 is secreted from cells in an inactive, latent form and stored as part of a large complex in the ECM. Various extracellular cues can result in the activation of TGF-β1 during which the active subunit of the protein breaks away from the latent complex. This active form then binds to and activates the TGF-β serine/threonine kinase receptors. These receptors then function through a canonical signaling pathway to modulate a wide variety of cellular processes such as apoptosis, proliferation, and differentiation by signaling through a family of transcription factors known as Smads.71
Thioredoxin-Based Peptide Aptamers: Development and Applications
Published in Rakesh N. Veedu, Aptamers, 2017
David S. Burz, Sergey Reverdatto, Alexander Shekhtman
Cui et al. [68] employed rational design to introduce PAs derived from the interaction motifs of Smad-binding proteins CBP (49 amino acids), FoxH1 (24 amino acids), and Lef1 (tandem duplication of 30 amino acids) into the TrxA scaffold to inhibit transforming growth factor beta (TGF-β)-induced gene expression. TGF-β alters gene expression by activating type I serine kinase receptors, which, in turn, phosphorylate Smad2 and Smad 3. Smad2 and Smad 3 form heterooligomeric complexes with Smad4 that accumulate in the nucleus and bind > 20 nuclear transcription factors, including CBP, FoxH1, and Lef1. These specific interactions give rise to the cell-type-specific effects of stimulating TGF-β gene expression, such as proliferation, apoptosis, and differentiation. The three PAs examined bind specifically to Smads and differentially inhibit TGF-β-induced gene expression in HepG2 cells.
Agrochemical-mediated cardiotoxicity in zebrafish embryos/larvae: What we do and where we go
Published in Critical Reviews in Environmental Science and Technology, 2023
Yang Yang, Yue Tao, Zixu Li, Yunhe Cui, Jinzhu Zhang, Ying Zhang
Normal expression of the bone morphogenetic protein (BMP) signaling pathway is also essential to the development of the central nervous, skeletal and cardiovascular systems (Massague et al., 2000; Pater et al., 2012). In zebrafish, BMP ligands initially bind to the type II receptor and recruit type I, whereby type II receptors phosphorylate and activate type I. In turn the type I receptor, phosphorylates receptor-activated Smads. Once phosphorylated, receptor-activated Smads associate with Smad4; the associated proteins are translocated into the nucleus and activate the expression of downstream genes (Laux et al., 2011) (Figure 3). The negative feedback modality also exists in the BMP signaling pathway, in which Smad6 can block binding of Smad1 to Smad4 by forming an inactive complex with Smad1. Moreover, Smad7 directly interacts with activated type I receptors, thus preventing the activation of receptor-activated Smads (Kruithof et al., 2012). Laf/alk8 zebrafish mutants (BMP type I receptor deletion) exhibit a reduced cardiomyocyte abundance and failure of cardiac looping at 48 hpf, whereas re-expression of alk8 at different times has different effects on recovery of the above defects. These results suggest that the BMP signaling pathway regulates cardiac looping and cardiomyocyte differentiation independently and at different stages (Pater et al., 2012).
3D printing silk-gelatin-propanediol scaffold with enhanced osteogenesis properties through p-Smad1/5/8 activated Runx2 pathway
Published in Journal of Biomaterials Science, Polymer Edition, 2021
Caiyun Liu, Zhenzu Bai, Jiayu Lin, Kai Jiang, Shan Huang, Weijia Zheng, Ruifen Chen, Yang Xiang, Xiaoyan Wang, Long Liu
The phosphorylated Smad protein can transfer into the nucleus and play an important role as a transcription factor, activating the downstream target genes to regulate bone formation [26]. Erk is the key factor to transfer the signal from receptors to the nucleus. This signaling pathway regulates cell growth, differentiation and division. Phosphorylated Erk1/2 could mediate transcriptional activation of downstream target genes [27]. In this study, the results showed that the phosphorylation levels of Smad1/5/8 protein were significantly higher in MC3T3-E1 cells cultured on S-Gel-PG25 and S-Gel-PG30 scaffolds than the cells cultured on S-Gel-Gly25 and S-Gel-Ery25 scaffolds (Figure 5A and 5B), while there is no significant difference in p-Erk1/2 expression among MC3T3-E1 cells cultured on S-Gel-PG25 and S-Gel-PG30 scaffolds as well as the cells cultured on S-Gel-Gly25 scaffold (Figure 5C and 5D). Therefore, these data indicated that S-Gel-PG25 and S-Gel-PG30 scaffolds may enhance the proliferation, differentiation and mineralization of MC3T3-E1 cells through p-Smad1/5/8 pathway, but not p-Erk1/2 pathway.
Transcriptome analysis of Takifugu obscurus liver in response to acute retene exposure
Published in Journal of Environmental Science and Health, Part A, 2020
Shulun Jiang, Di-an Fang, Dongpo Xu
The SMAD family regulates intracellular events of the transforming growth factor β (TGFβ) signaling pathway, which controls cellular processes involving cell proliferation, differentiation, apoptosis, and tumorigenesis.[62] SMAD4 mediates TGF-beta activities and regulates the actions of all the R-SMADs.[63] SMAD4 is needed for gastrulation and acts to suppress gastric cancer in mice.[64] Moreover, SMAD3 also participates in tumorigenesis, immune response, and the skeleton development of mice.[64] Following retene exposure, unusual activation of the FOXO pathway may be attributed to an immune response or to cell repair. Moreover, overactivation of FOXO pathways may distrupt the normal cycle and result in an increased risk of tumorigenesis.