The mechanism of TGF-β/miR-155/c-Ski regulates endothelial–mesenchymal transition in human coronary artery endothelial cells

Wang, Juan; He, Wen; Xu, Xiao Hui; Guo, Liping; Zhang, Ying; Han, Suxia; Shen, Difei

doi:10.1042/bsr20160603

Cited by 35 publications

(18 citation statements)

References 44 publications

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“…In addition, previous studies have reported that low TGF-β1 concentrations promote the proliferation of muscle, bone (or chondrocytes) and endothelial cells [4,17]. In addition, c-Ski can promote muscle proliferation [18] and participates in endothelial, chondrocyte proliferation [19,20]; c-Ski knockout mice and c-Ski-deficient individuals have defective bone and muscle development [21]. Therefore, these results indicate that proliferation of these cells induced by low TGF-β1 concentrations may also be mediated through the induction of c-Ski.…”

Section: Low Tgf-β1 Concentrations Promote Skin Fibroblast Proliferatmentioning

confidence: 98%

The ERK/CREB pathway is involved in the c-Ski expression induced by low TGF-β1 concentrations during primary fibroblast proliferation

Liu

Peng

et al. 2018

Cell Cycle

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Increasing evidence has suggested that bidirectional regulation of cell proliferation is one important effect of TGF-β1 in wound healing. Increased c-Ski expression plays a role in promoting fibroblast proliferation at low TGF-β1 concentrations, but the mechanism by which low TGF-β1 concentrations regulate c-Ski levels remains unclear. In this study, the proliferation of rat primary fibroblasts was assessed with an ELISA BrdU kit. The mRNA and protein expression and phosphorylation levels of corresponding factors were measured by RT-qPCR, immunohistochemistry or Western blotting. We first found that low TGF-β1 concentrations not only promoted c-ski mRNA and protein expression in rat primary fibroblasts but also increased the phosphorylation levels of Extracellular Signal-Regulated Kinases (ERK) and cAMP response element binding (CREB) protein. An ERK kinase (mitogen-activated protein kinase kinase, MEK) inhibitor significantly inhibited ERK1/2 phosphorylation levels, markedly reducing c-Ski expression and CREB phosphorylation levels and abrogating the growth-promoting effect of low TGF-β1 concentrations. At the same time, Smad2/3 phosphorylation levels were not significantly changed. Taken together, these results suggest that the increased cell proliferation induced by low TGF-β1 concentrations mediates c-Ski expression potentially through the ERK/CREB pathway rather than through the classic TGF-β1/Smad pathway.

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Section: Low Tgf-β1 Concentrations Promote Skin Fibroblast Proliferatmentioning

confidence: 98%

The ERK/CREB pathway is involved in the c-Ski expression induced by low TGF-β1 concentrations during primary fibroblast proliferation

Liu

Peng

et al. 2018

Cell Cycle

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“…Importantly, Ski overexpression inhibits the TGF-β-induced EndMT of HCAECs via a mechanism that involves the regulation of miR-155. 107 During liver fibrogenesis induced by TGF-β and acetaldehyde, an ethanol metabolite, increased collagen synthesis occurs in hepatic stellate cells (HSC); in these cells, the Ski/Smad4 complex is translocated to the cytoplasm, and the Ski protein is degraded via UPS. 244 In systemic sclerosis, the levels of the Ski and SnoN proteins are increased in scleroderma fibroblasts, although they fail to inhibit the TGF-β pathway because they are unable to compete with the p300 coactivator.…”

Section: Regulation Of Tgf-β/smad Signaling By Ski and Snonmentioning

confidence: 99%

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

Tecalco-Cruz

Ríos-López

Vázquez‐Victorio

et al. 2018

Sig Transduct Target Ther

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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.

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“…15,16 Thus, understanding the pathogenesis of cardiac fibrosis may identify promising targets for the treatment of patients with AF. 20 Zhang et al found that c-Ski can ameliorate isoproterenol-induced myocardial fibrosis in a rat model and reduce both TGF-β1-induced proliferation of primary rat cardiac fibroblasts and ECM deposition. [17][18][19] Recently, researchers have focused on the effects of c-Ski in cardiac fibrosis.…”

Section: Discussionmentioning

confidence: 99%

“…Studies also suggest that the c-Ski protein plays an important role in the development of nerve and muscle as well as in organ fibrosis. [17][18][19] Recently, researchers have focused on the ef- 20 Zhang et al found that c-Ski can ameliorate isoproterenol-induced myocardial fibrosis in a rat model and reduce both TGF-β1-induced proliferation of primary rat cardiac fibroblasts and ECM deposition. 19 Our team previously determined the involvement of c-Ski in the regulation of TGF-β-induced proliferation of human cardiac fibroblasts and ECM protein expression.…”

Section: Discussionmentioning

confidence: 99%

Effect of c‐Ski on atrial remodelling in a rapid atrial pacing canine model

Wang

Han²,

Han

et al. 2019

J Cellular Molecular Medi

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Atrial fibrosis is an important factor in the initiation and maintenance of atrial fibrillation (AF); therefore, understanding the pathogenesis of atrial fibrosis may reveal promising therapeutic targets for AF. In this study, we successfully established a rapid atrial pacing canine model and found that the inducibility and duration of AF were significantly reduced by the overexpression of c‐Ski, suggesting that this approach may have therapeutic effects. c‐Ski was found to be down‐regulated in the atrial tissues of the rapid atrial pacing canine model. We artificially up‐regulated c‐Ski expression with a c‐Ski–overexpressing adenovirus. Haematoxylin and eosin, Masson's trichrome and picrosirius red staining showed that c‐Ski overexpression alleviated atrial fibrosis. Furthermore, we found that the expression levels of collagen III and α‐SMA were higher in the groups of dogs subjected to right‐atrial pacing, and this increase was attenuated by c‐Ski overexpression. In addition, c‐Ski overexpression decreased the phosphorylation of smad2, smad3 and p38 MAPK (p38α and p38β) as well as the expression of TGF‐β1 in atrial tissues, as shown by a comparison of the right‐atrial pacing + c‐Ski‐overexpression group to the control group with right‐atrial pacing only. These results suggest that c‐Ski overexpression improves atrial remodelling in a rapid atrial pacing canine model by suppressing TGF‐β1–Smad signalling and p38 MAPK activation.

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The mechanism of TGF-β/miR-155/c-Ski regulates endothelial–mesenchymal transition in human coronary artery endothelial cells

Cited by 35 publications

References 44 publications

The ERK/CREB pathway is involved in the c-Ski expression induced by low TGF-β1 concentrations during primary fibroblast proliferation

The ERK/CREB pathway is involved in the c-Ski expression induced by low TGF-β1 concentrations during primary fibroblast proliferation

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

Effect of c‐Ski on atrial remodelling in a rapid atrial pacing canine model

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