scholarly journals OTUD4 enhances TGFβ signalling through regulation of the TGFβ receptor complex

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Patrick William Jaynes ◽  
Prasanna Vasudevan Iyengar ◽  
Sarah Kit Leng Lui ◽  
Tuan Zea Tan ◽  
Natali Vasilevski ◽  
...  
Keyword(s):  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Negative Regulator ◽  
Deubiquitinating Enzyme ◽  
Tgfβ Receptor ◽  
Tgfβ Signalling ◽  
Systematic Control ◽  
General Regulation ◽  
Tgfβ Pathway ◽  
Transcriptional Target

Abstract Systematic control of the transforming growth factor-β (TGFβ) pathway is essential to keep the amplitude and the intensity of downstream signalling at appropriate levels. Ubiquitination plays a crucial role in the general regulation of this pathway. Here we identify the deubiquitinating enzyme OTUD4 as a transcriptional target of the TGFβ pathway that functions through a positive feedback loop to enhance overall TGFβ activity. Interestingly we demonstrate that OTUD4 functions through both catalytically dependent and independent mechanisms to regulate TGFβ activity. Specifically, we find that OTUD4 enhances TGFβ signalling by promoting the membrane presence of TGFβ receptor I. Furthermore, we demonstrate that OTUD4 inactivates the TGFβ negative regulator SMURF2 suggesting that OTUD4 regulates multiple nodes of the TGFβ pathway to enhance TGFβ activity.

Early cell changes and TGFβ pathway alterations in the aortopathy associated with bicuspid aortic valve stenosis

2012 ◽  
Vol 124 (2) ◽  
pp. 97-108 ◽  
Author(s):  
Amalia Forte ◽  
Alessandro Della Corte ◽  
Mario Grossi ◽  
Ciro Bancone ◽  
Raffaela Provenzano ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Aortic Valve ◽  
Bicuspid Aortic Valve ◽  
Transforming Growth Factor ◽  
Smooth Muscle Actin ◽  
Transforming Growth Factor Β ◽  
Cell Phenotype ◽  
Tgfβ Receptor ◽  
Lesser Curvature ◽  
Tgfβ Pathway

Previous studies on BAV (bicuspid aortic valve)-related aortopathy, whose aetiology is still debated, have focused mainly on severe dilatations. In the present study, we aimed to detect earlier signs of aortopathy. Specimens were collected from the ‘concavity’ (lesser curvature) and the ‘convexity’ (greater curvature) of mildly dilated AAs (ascending aortas; diameter ≤4 cm) with stenotic TAV (tricuspid aortic valve) or BAV and from donor normal aortas. Specimens were submitted to morphometry, immunohistochemistry and differential gene-expression analysis, focusing on SMC (smooth muscle cell) phenotype, remodelling, MF (myofibroblast) differentiation and TGFβ (transforming growth factor β) pathway. Smoothelin and myocardin mRNAs decreased in all the samples from patients, with the exception of those from BAV convexity, where a change in orientation of smoothelin-positive SMCs and an increase of α-SMA (α-smooth muscle actin) mRNA occurred. Dilated aortas from BAV and TAV patients showed both shared and distinct alterations concerning the TGFβ pathway, including an increased TGFβ and TGFβR2 (TGFβ receptor 2) expression in both groups and a decreased TGFβR1 expression in BAV samples only. Despite a decrease of the mRNA coding for the ED-A (extra domain-A) isoform of FN (fibronectin) in the BAV convexity, the onset of the expression of the corresponding protein in the media was observed in dilated aortas, whereas the normal media from donors was negative for this isoform. This discrepancy could be related to modifications in the intima, normally expressing ED-A FN and showing an altered structure in mild aortic dilatations in comparison with donor aorta. Our results suggest that changes in SMC phenotype and, likely, MF differentiation, occur early in the aortopathy associated with valve stenosis. The defective expression of TGFβR1 in BAV might be a constitutive feature, while other changes we reported could be influenced by haemodynamics.

scholarly journals Obesity-associated extracellular mtDNA activates central TGFβ pathway to cause blood pressure increase

2017 ◽  
Vol 312 (3) ◽  
pp. E161-E174 ◽  
Author(s):  
Albert Alé ◽  
Yalin Zhang ◽  
Cheng Han ◽  
Dongsheng Cai
Keyword(s):  
Receptor Antagonist ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Central Administration ◽  
Downstream Signaling ◽  
Inflammatory Mechanism ◽  
Tgfβ Receptor ◽  
Hypothalamic Inflammation ◽  
Dietary Obesity ◽  
Tgfβ Pathway

Hypothalamic inflammation was recently found to mediate obesity-related hypertension, but the responsible upstream mediators remain unexplored. In this study, we show that dietary obesity is associated with extracellular release of mitochondrial DNA (mtDNA) into the cerebrospinal fluid and that central delivery of mtDNA mimics transforming growth factor-β (TGFβ) excess to activate downstream signaling pathways. Physiological study reveals that central administration of mtDNA or TGFβ is sufficient to cause hypertension in mice. Knockout of the TGFβ receptor in proopiomelanocortin neurons counteracts the hypertensive effect of not only TGFβ but also mtDNA excess, while the hypertensive action of central mtDNA can be blocked pharmacologically by a TGFβ receptor antagonist or genetically by TGFβ receptor knockout. Finally, we confirm that obesity-induced hypertension can be reversed through central treatment with TGFβ receptor antagonist. In conclusion, circulating mtDNA in the brain employs neural TGFβ pathway to mediate a central inflammatory mechanism of obesity-related hypertension.

scholarly journals TGFβ induces SIK to negatively regulate type I receptor kinase signaling

2008 ◽  
Vol 182 (4) ◽  
pp. 655-662 ◽  
Author(s):  
Marcin Kowanetz ◽  
Peter Lönn ◽  
Michael Vanlandewijck ◽  
Katarzyna Kowanetz ◽  
Carl-Henrik Heldin ◽  
...  
Keyword(s):  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Cell Types ◽  
Negative Regulator ◽  
Type I ◽  
Gene Target ◽  
Smad Proteins ◽  
Tgfβ Receptor ◽  
Receptor Kinase Signaling ◽  
Feedback Program

Signal transduction by transforming growth factor β (TGFβ) coordinates physiological responses in diverse cell types. TGFβ signals via type I and type II receptor serine/threonine kinases and intracellular Smad proteins that regulate transcription. Strength and duration of TGFβ signaling is largely dependent on a negative-feedback program initiated during signal progression. We have identified an inducible gene target of TGFβ/Smad signaling, the salt-inducible kinase (SIK), which negatively regulates signaling together with Smad7. SIK and Smad7 form a complex and cooperate to down-regulate the activated type I receptor ALK5. We further show that both the kinase and ubiquitin-associated domain of SIK are required for proper ALK5 degradation, with ubiquitin functioning to enhance SIK-mediated receptor degradation. Loss of endogenous SIK results in enhanced gene responses of the fibrotic and cytostatic programs of TGFβ. We thus identify in SIK a negative regulator that controls TGFβ receptor turnover and physiological signaling.

scholarly journals Transforming growth factor beta signaling in hepatocellular carcinoma: as a victim or culprit?

2019 ◽  
Vol 6 (3) ◽  
pp. 991
Author(s):  
Varun Kumar Sharma ◽  
Charu Tyagi ◽  
Yugandhar P. Reddy ◽  
Jayanand Manjhi ◽  
Lomas Kumar Tomar
Keyword(s):  
Hepatocellular Carcinoma ◽  
Growth Factor ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Signalling Pathway ◽  
Expression Of Genes ◽  
Tgfβ Signalling ◽  
Growth Factor Beta ◽  
Tgfβ Pathway

The transforming growth factor-β (TGFβ) signalling pathway control various cellular function and play a pivotal role in tumour suppression. In contrary, overexpression of TGFβ is linked to promote the cancer development. TGFβ facilitate cell-growth and cell-differentiation process which support tumour propagation. In case of hepatocellular carcinoma (HCC), TGFβ signalling pathway is the master regulator of HCCs pathogenesis and functionally involved in the regulation of HCCs phenotype via modulating the downstream signalling pathways. In this article, we have highlighted the contradictory behaviour of TGFβ in hepatocellular carcinoma. Observations suggest that the TGFβ signalling pathway is positively correlated to the expression of genes linked with various hepatic pathological conditions, including fibrosis, cirrhosis, inflammation and cancer. TGFβ pathway play dual role as pro and anti-tumoural activities in cancer cells depending on their context.

scholarly journals Skeletal Deformities in Osterix-Cre;Tgfbr2f/f Mice May Cause Postnatal Death

Genes ◽  
2021 ◽  
Vol 12 (7) ◽  
pp. 975
Author(s):  
Kara Corps ◽  
Monica Stanwick ◽  
Juliann Rectenwald ◽  
Andrew Kruggel ◽  
Sarah B. Peters
Keyword(s):  
Transforming Growth Factor ◽  
Skeletal Development ◽  
Transforming Growth Factor Β ◽  
Tgfβ Signaling ◽  
Skeletal Deformities ◽  
Tooth Abnormalities ◽  
Pathological Analysis ◽  
Diaphragmatic Muscle ◽  
Proliferation And Differentiation ◽  
Tgfβ Receptor

Transforming growth factor β (TGFβ) signaling plays an important role in skeletal development. We previously demonstrated that the loss of TGFβ receptor II (Tgfbr2) in Osterix-Cre-expressing mesenchyme results in defects in bones and teeth due to reduced proliferation and differentiation in pre-osteoblasts and pre-odontoblasts. These Osterix-Cre;Tgfbr2f/f mice typically die within approximately four weeks for unknown reasons. To investigate the cause of death, we performed extensive pathological analysis on Osterix-Cre- (Cre-), Osterix-Cre+;Tgfbr2f/wt (HET), and Osterix-Cre+;Tgfbr2f/f (CKO) mice. We also crossed Osterix-Cre mice with the ROSA26mTmG reporter line to identify potential off-target Cre expression. The findings recapitulated published skeletal and tooth abnormalities and revealed previously unreported osteochondral dysplasia throughout both the appendicular and axial skeletons in the CKO mice, including the calvaria. Alterations to the nasal area and teeth suggest a potentially reduced capacity to sense and process food, while off-target Cre expression in the gastrointestinal tract may indicate an inability to absorb nutrients. Additionally, altered nasal passages and unexplained changes in diaphragmatic muscle support the possibility of hypoxia. We conclude that these mice likely died due to a combination of breathing difficulties, malnutrition, and starvation resulting primarily from skeletal deformities that decreased their ability to sense, gather, and process food.

scholarly journals Expression and function of Smad7 in autoimmune and inflammatory diseases

2021 ◽  
Author(s):  
Yiping Hu ◽  
Juan He ◽  
Lianhua He ◽  
Bihua Xu ◽  
Qingwen Wang
Keyword(s):  
Posttranscriptional Regulation ◽  
Molecular Mechanisms ◽  
Transforming Growth Factor ◽  
Inflammatory Diseases ◽  
Kidney Diseases ◽  
Critical Role ◽  
Transforming Growth Factor Β ◽  
Negative Regulator ◽  
Signaling Mechanism ◽  
And Function

AbstractTransforming growth factor-β (TGF-β) plays a critical role in the pathological processes of various diseases. However, the signaling mechanism of TGF-β in the pathological response remains largely unclear. In this review, we discuss advances in research of Smad7, a member of the I-Smads family and a negative regulator of TGF-β signaling, and mainly review the expression and its function in diseases. Smad7 inhibits the activation of the NF-κB and TGF-β signaling pathways and plays a pivotal role in the prevention and treatment of various diseases. Specifically, Smad7 can not only attenuate growth inhibition, fibrosis, apoptosis, inflammation, and inflammatory T cell differentiation, but also promotes epithelial cells migration or disease development. In this review, we aim to summarize the various biological functions of Smad7 in autoimmune diseases, inflammatory diseases, cancers, and kidney diseases, focusing on the molecular mechanisms of the transcriptional and posttranscriptional regulation of Smad7.

scholarly journals ROS and TGFβ: from pancreatic tumour growth to metastasis

2021 ◽  
Vol 40 (1) ◽  
Author(s):  
Chao-Hui Chang ◽  
Siim Pauklin
Keyword(s):  
Tumour Growth ◽  
Cancer Metastasis ◽  
Transforming Growth Factor ◽  
Cancer Therapeutics ◽  
Transforming Growth Factor Β ◽  
Ductal Adenocarcinoma ◽  
Cellular Processes ◽  
Tumour Development ◽  
Pancreatic Tumour ◽  
Tgfβ Signalling

AbstractTransforming growth factor β (TGFβ) signalling pathway switches between anti-tumorigenic function at early stages of cancer formation and pro-tumorigenic effects at later stages promoting cancer metastasis. A similar contrasting role has been uncovered for reactive oxygen species (ROS) in pancreatic tumorigenesis. Down-regulation of ROS favours premalignant tumour development, while increasing ROS level in pancreatic ductal adenocarcinoma (PDAC) enhances metastasis. Given the functional resemblance, we propose that ROS-mediated processes converge with the spatial and temporal activation of TGFβ signalling and thereby differentially impact early tumour growth versus metastatic dissemination. TGFβ signalling and ROS could extensively orchestrate cellular processes and this concerted function can be utilized by cancer cells to facilitate their malignancy. In this article, we revisit the interplay of canonical and non-canonical TGFβ signalling with ROS throughout pancreatic tumorigenesis and metastasis. We also discuss recent insight that helps to understand their conflicting effects on different stages of tumour development. These considerations open new strategies in cancer therapeutics.

scholarly journals Vascular consequences of dietary salt intake

2009 ◽  
Vol 297 (2) ◽  
pp. F237-F243 ◽  
Author(s):  
Paul W. Sanders
Keyword(s):  
Nitric Oxide ◽  
Renal Function ◽  
Life Span ◽  
Vascular Function ◽  
Transforming Growth Factor ◽  
Salt Intake ◽  
Transforming Growth Factor Β ◽  
Negative Regulator ◽  
Dietary Salt ◽  
Dietary Salt Intake

Animal and human studies support an untoward effect of excess dietary NaCl (salt) intake on cardiovascular and renal function and life span. Recent work has promoted the concept that the endothelium, in particular, reacts to changes in dietary salt intake through a complex series of events that are independent of blood pressure and the renin-angiotensin-aldosterone axis. The cellular signaling events culminate in the intravascular production of transforming growth factor-β (TGF-β) and nitric oxide in response to increased salt intake. Plasticity of the endothelium is integral in the vascular remodeling consequences associated with excess salt intake, because nitric oxide serves as a negative regulator of TGF-β production. Impairment of nitric oxide production, such as occurs with endothelial dysfunction in a variety of disease states, results in unopposed excess vascular TGF-β production, which promotes reduced vascular compliance and augmented peripheral arterial constriction and hypertension. Persistent alterations in vascular function promote the increase in cardiovascular events and reductions in renal function that reduce life span during increased salt intake.

Myostatin-induced inhibition of the long noncoding RNA Malat1 is associated with decreased myogenesis

2013 ◽  
Vol 304 (10) ◽  
pp. C995-C1001 ◽  
Author(s):  
Rani Watts ◽  
Virginia L. Johnsen ◽  
Jane Shearer ◽  
Dustin S. Hittel
Keyword(s):  
Gene Expression ◽  
Skeletal Muscle ◽  
Cell Growth ◽  
Noncoding Rna ◽  
Transforming Growth Factor ◽  
Day Treatment ◽  
Global Gene Expression ◽  
Transforming Growth Factor Β ◽  
Negative Regulator ◽  
Human Skeletal Muscle Cells

Myostatin, a member of the transforming growth factor-β (TGF-β) superfamily of secreted proteins, is a potent negative regulator of myogenesis. Free myostatin induces the phosphorylation of the Smad family of transcription factors, which, in turn, regulates gene expression, via the canonical TGF-β signaling pathway. There is, however, emerging evidence that myostatin can regulate gene expression independent of Smad signaling. As such, we acquired global gene expression data from the gastrocnemius muscle of C57BL/6 mice following a 6-day treatment with recombinant myostatin compared with vehicle-treated animals. Of the many differentially expressed genes, the myostatin-associated decrease (−11.20-fold; P < 0.05) in the noncoding metastasis-associated lung adenocarcinoma transcript 1 (Malat1) was the most significant and the most intriguing because of numerous reports describing its novel role in regulating cell growth. We therefore sought to further characterize the role of Malat1 expression in skeletal muscle myogenesis. RT-PCR-based quantification of C2C12 and primary human skeletal muscle cells revealed a significant and persistent upregulation (4- to 7-fold; P < 0.05) of Malat1 mRNA during the differentiation of myoblasts into myotubes. Conversely, targeted knockdown of Malat1 using siRNA suppressed myoblast proliferation by arresting cell growth in the G0/G1phase. These results reveal Malat1 as novel downstream target of myostatin with a considerable ability to regulate myogenesis. The identification of new targets of myostatin will have important repercussions for regenerative biology through inhibition and/or reversal of muscle atrophy and wasting diseases.

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