TGF-β/TGF-β receptor system and its role in physiological and pathological conditions

Santibáñez, Juan F.; Quintanilla, Miguel; Bernabeu, Carmelo

doi:10.1042/cs20110086

Cited by 345 publications

(323 citation statements)

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“…TGF-b binds to TbRII, which recruits the TbRI, ALK5. 23,24 Considering this evidence, we investigated whether ALK5 expression was involved in the H 2 O 2 -induced conversion of ECs into myofibroblasts. To that end, we performed experiments using a molecular biology strategy for ALK5 expression knockdown.…”

Section: H 2 O 2 -Induced Conversion Of Ecs Into Myofibroblasts Is Dementioning

confidence: 99%

“…Specifically, Smad3 phosphorylation has been linked to the fibrotic Oxidative stress-mediated EC fibrosis via TGF-b I Montorfano et al process. 23,24 Thus, we addressed the question of whether Smad3 activation participates in the H 2 O 2 -induced conversion of ECs into myofibroblasts. To that purpose, we used the specific inhibitor of Smad3, SIS3.…”

Section: H 2 O 2 -Induced Conversion Of Ecs Into Myofibroblasts Is Dementioning

confidence: 99%

“…Taking into consideration that TGF-b expression is dependent on p38 MAPK phosphorylation, 6,24 we studied whether H 2 O 2 induces the increased phosphorylation of p38 MAPK. H 2 O 2 exposure induced p38 MAPK phosphorylation showing a peak at 1 h after challenge (Supplementary Figure S3).…”

Section: H 2 O 2 -Induced Conversion Of Ecs Into Myofibroblasts Is Dementioning

confidence: 99%

“…[19][20][21][22] TGF-b binds its plasma membrane receptor, activin receptor-like kinase 5 (ALK5), to activate it and subsequently elicit intracellular signaling. 23,24 Several proteins that are involved in TGF-b intracellular signaling include the canonical pathway of phosphorylation of the family of Smad proteins and non-canonical intracellular pathways, to perform the activation of nuclear factor-kappa B (NF-kB). [24][25][26][27][28] Specifically, the Smad3 protein emerges as a pro-fibrotic member of the Smad protein family because its phosphorylation promotes the progression of fibrosis.…”

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confidence: 99%

“…23,24 Several proteins that are involved in TGF-b intracellular signaling include the canonical pathway of phosphorylation of the family of Smad proteins and non-canonical intracellular pathways, to perform the activation of nuclear factor-kappa B (NF-kB). [24][25][26][27][28] Specifically, the Smad3 protein emerges as a pro-fibrotic member of the Smad protein family because its phosphorylation promotes the progression of fibrosis. 29,30 It has been reported that oxidative stress induces the EMT.…”

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confidence: 99%

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Oxidative stress mediates the conversion of endothelial cells into myofibroblasts via a TGF-β1 and TGF-β2-dependent pathway

Montorfano

Becerra

Cerro

et al. 2014

Laboratory Investigation

116

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During the pathogenesis of systemic inflammation, reactive oxygen species (ROS) circulate in the bloodstream and interact with endothelial cells (ECs), increasing intracellular oxidative stress. Although endothelial dysfunction is crucial in the pathogenesis of systemic inflammation, little is known about the effects of oxidative stress on endothelial dysfunction. Oxidative stress induces several functions, including cellular transformation. A singular process of cell conversion is tendothelial-to-mesenchymal transition, in which ECs become myofibroblasts, thus losing their endothelial properties and gaining fibrotic behavior. However, the participation of oxidative stress as an inductor of conversion of ECs into myofibroblasts is not known. Thus, we studied the role played by oxidative stress in this conversion and investigated the underlying mechanism. Our results show that oxidative stress induces conversion of ECs into myofibroblasts through decreasing the levels of endothelial markers and increasing those of fibrotic and ECM proteins. The underlying mechanism depends on the ALK5/Smad3/NF-kB pathway. Oxidative stress induces the expression and secretion of TGF-b1 and TGF-b2 and p38 MAPK phosphorylation. Downregulation of TGF-b1 and TGF-b2 by siRNA technology abolished the H 2 O 2 -induced conversion. To our knowledge, this is the first report showing that oxidative stress is able to induce conversion of ECs into myofibroblasts via TGF-b secretion, emerging as a source for oxidative stress-based vascular dysfunction. Thus, oxidative stress emerges as a decisive factor in inducing conversion of ECs into myofibroblasts through a TGF-b-dependent mechanism, changing the ECs protein expression profile, and converting normal ECs into pathological ones. This information will be useful in designing new and improved therapeutic strategies against oxidative stress-mediated systemic inflammatory diseases.

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Section: H 2 O 2 -Induced Conversion Of Ecs Into Myofibroblasts Is Dementioning

confidence: 99%

Section: H 2 O 2 -Induced Conversion Of Ecs Into Myofibroblasts Is Dementioning

confidence: 99%

Section: H 2 O 2 -Induced Conversion Of Ecs Into Myofibroblasts Is Dementioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Oxidative stress mediates the conversion of endothelial cells into myofibroblasts via a TGF-β1 and TGF-β2-dependent pathway

Montorfano

Becerra

Cerro

et al. 2014

Laboratory Investigation

116

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TGF ‐β Signalling and Its Role in Cancer Progression and Metastasis

Santibáñez

Krstić

Quintanilla

et al. 2016

Encyclopedia of Life Sciences

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Normal body cells grow, proliferate and die in an orderly manner. By contrast, cancer cells grow out of control and can invade other tissues. The process of tumour progression and metastasis results from a complex molecular cascade that allows cancer cells to leave the site of the primary tumour mass and disseminate to distant anatomical sites where they proliferate and form secondary tumour foci. Disseminated disease is the most usual cause of death in cancer patients and is, therefore, a very serious clinical problem. Transforming growth factor beta (TGF‐β) has a dual role in tumour progression, acting as a tumour suppressor in early stages of carcinogenesis, and exerting a pro‐oncogenic role in the last steps of metastatic disease. TGF‐β induces the epithelial mesenchymal transition of transformed cells, which contributes to tumour invasion and metastasis, and is frequently overexpressed in cancer cells. Key Concepts TGF‐βs and their signalling components are widely expressed in all tissues and play a major role in human diseases. The canonical signalling pathway triggered by TGF‐βs involves the activation of Smad proteins by the TGF‐β receptors and their translocation into the nucleus. In addition, TGF‐β receptors can activate Smad‐independent (non‐canonical) pathways, including MAPKs and Rho GTPases, among others. Canonical and noncanonical TGF‐β signal transduction participates in and explains the broad spectrum of TGF‐β effects on tumour progression. TGF‐β is postulated as a dual factor in cancer since it can act either as a tumour suppressor in early stages of tumourigenesis or as a tumour promoter in late stages of tumour progression. One of the hallmarks at late stages of tumour progression is that cancer cells become refractory to the TGF‐β cell growth inhibitory response. Many types of cancer cells leaving primary carcinomas appear to depend on EMT to facilitate execution of most of the steps of the invasion–metastasis process. TGF‐β affects not only the tumour cells themselves but also the surrounding stroma by inhibiting cell adhesion, inducing immunosuppression and angiogenesis, and by promoting the degradation of the extracellular matrix, further modulating the metastatic process. Induction of EMT by TGF‐β generates cancer cells with stem‐like properties. By regulating TGF‐β expression and its canonical and noncanonical intracellular signalling, it may be possible to control the tumour microenvironment, including angiogenesis, immunosurveillance escape and activation of stromal fibroblasts resulting in cancer‐associated fibroblasts (CAFs), tumour‐stroma interactions and EMT.

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