scholarly journals LncRNA GAS5 attenuates fibroblast activation through inhibiting Smad3 signaling

2020 ◽  
Vol 319 (1) ◽  
pp. C105-C115
Author(s):  
Rui Tang ◽  
Yung-Chun Wang ◽  
Xiaohan Mei ◽  
Ning Shi ◽  
Chenming Sun ◽  
...  
Keyword(s):  
Protein Phosphatase ◽  
Noncoding Rna ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Molecular Processes ◽  
Cultured Fibroblasts ◽  
Fibroblast Activation ◽  
Fibrotic Diseases ◽  
Smad3 Binding ◽  
Pathological Event

Transforming growth factor-β (TGF-β)-induced fibroblast activation is a key pathological event during tissue fibrosis. Long noncoding RNA (lncRNA) is a class of versatile gene regulators participating in various cellular and molecular processes. However, the function of lncRNA in fibroblast activation is still poorly understood. In this study, we identified growth arrest-specific transcript 5 (GAS5) as a novel regulator for TGF-β-induced fibroblast activation. GAS5 expression was downregulated in cultured fibroblasts by TGF-β and in resident fibroblasts from bleomycin-treated skin tissues. Overexpression of GAS5 suppressed TGF-β-induced fibroblast to myofibroblast differentiation. Mechanistically, GAS5 directly bound mothers against decapentaplegic homolog 3 (Smad3) and promoted Smad3 binding to Protein phosphatase 1A (PPM1A), a Smad3 dephosphatase, and thus accelerated Smad3 dephosphorylation in TGF-β-treated fibroblasts. In addition, GAS5 inhibited fibroblast proliferation. Importantly, local delivery of GAS5 via adenoviral vector suppressed bleomycin-induced skin fibrosis in mice. Collectively, our data revealed that GAS5 suppresses fibroblast activation and fibrogenesis through inhibiting TGF-β/Smad3 signaling, which provides a rationale for an lncRNA-based therapy to treat fibrotic diseases.

scholarly journals LncRNA GAS5 attenuates fibroblast activation through inhibiting Smad3 signaling

2020 ◽  
Author(s):  
Rui Tang ◽  
Yung-Chun Wang ◽  
Xiaohan Mei ◽  
Ning Shi ◽  
Chengming Sun ◽  
...  
Keyword(s):  
Noncoding Rna ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Fibroblast Proliferation ◽  
Molecular Processes ◽  
Cultured Fibroblasts ◽  
Fibroblast Activation ◽  
Fibrotic Diseases ◽  
Smad3 Binding ◽  
Pathological Event

AbstractTransforming Growth Factor β (TGF-β)-induced fibroblast activation is a key pathological event during tissue fibrosis. Long noncoding RNA (lncRNA) is a class of versatile gene regulators participating in various cellular and molecular processes. However, the function of lncRNA in fibroblast activation is still poorly understood. In this study, we identified growth arrest-specific transcript 5 (GAS5) as a novel regulator for TGF-β-induced fibroblast activation. GAS5 expression was downregulated in cultured fibroblasts by TGF-β and in resident fibroblasts from bleomycin-treated skin tissues. Overexpression of GAS5 suppressed TGF-β-induced fibroblast to myofibroblast differentiation. Mechanistically, GAS5 directly bound Smad3 and promoted Smad3 binding to PPM1A, a Smad3 dephosphatase, and thus accelerated Smad3 dephosphorylation in TGF-β-treated fibroblasts. In addition, GAS5 inhibited fibroblast proliferation. Importantly, local delivery of GAS5 via adenoviral vector suppressed bleomycin-induced skin fibrosis in mice. Collectively, our data revealed that GAS5 suppresses fibroblast activation and fibrogenesis through inhibiting TGF-β/Smad3 signaling, which provides a rationale for an lncRNA-based therapy to treat fibrotic diseases.

scholarly journals TGFβ promotes fibrosis by MYST1-dependent epigenetic regulation of autophagy

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Ariella Zehender ◽  
Yi-Nan Li ◽  
Neng-Yu Lin ◽  
Adrian Stefanica ◽  
Julian Nüchel ◽  
...  
Keyword(s):  
Tissue Repair ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Therapeutic Interventions ◽  
Epigenetic Mechanism ◽  
Tgfβ Signaling ◽  
Tissue Fibrosis ◽  
Fibroblast Activation ◽  
Core Components ◽  
Fibrotic Diseases

AbstractActivation of fibroblasts is essential for physiological tissue repair. Uncontrolled activation of fibroblasts, however, may lead to tissue fibrosis with organ dysfunction. Although several pathways capable of promoting fibroblast activation and tissue repair have been identified, their interplay in the context of chronic fibrotic diseases remains incompletely understood. Here, we provide evidence that transforming growth factor-β (TGFβ) activates autophagy by an epigenetic mechanism to amplify its profibrotic effects. TGFβ induces autophagy in fibrotic diseases by SMAD3-dependent downregulation of the H4K16 histone acetyltransferase MYST1, which regulates the expression of core components of the autophagy machinery such as ATG7 and BECLIN1. Activation of autophagy in fibroblasts promotes collagen release and is both, sufficient and required, to induce tissue fibrosis. Forced expression of MYST1 abrogates the stimulatory effects of TGFβ on autophagy and re-establishes the epigenetic control of autophagy in fibrotic conditions. Interference with the aberrant activation of autophagy inhibits TGFβ-induced fibroblast activation and ameliorates experimental dermal and pulmonary fibrosis. These findings link uncontrolled TGFβ signaling to aberrant autophagy and deregulated epigenetics in fibrotic diseases and may contribute to the development of therapeutic interventions in fibrotic diseases.

scholarly journals Tribbles homologue 3 stimulates canonical TGF-β signalling to regulate fibroblast activation and tissue fibrosis

2015 ◽  
Vol 75 (3) ◽  
pp. 609-616 ◽  
Author(s):  
Michal Tomcik ◽  
Katrin Palumbo-Zerr ◽  
Pawel Zerr ◽  
Barbora Sumova ◽  
Jerome Avouac ◽  
...  
Keyword(s):  
Cell Activation ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Dependent Manner ◽  
Cultured Fibroblasts ◽  
Fibroblast Activation ◽  
Modulation Of Gene Expression ◽  
Β Receptor ◽  
Interfering Rna

ObjectivesTribbles homologue 3 (TRB3) is a pseudokinase that modifies the activation of various intracellular signalling pathways to control fundamental processes extending from mitosis and cell activation to apoptosis and modulation of gene expression. Here, we aimed to analyse the role of TRB3 in fibroblast activation in systemic sclerosis (SSc).MethodsThe expression of TRB3 was quantified by quantitative PCR, western blot and immunohistochemistry. The role of TRB3 was analysed in cultured fibroblasts and in experimental fibrosis using small interfering RNA (siRNA)-mediated knockdown and overexpression of TRB3.ResultsTRB3 expression was increased in fibroblasts of patients with SSc and in murine models of SSc in a transforming growth factor-β (TGF-β)/Smad-dependent manner. Overexpression of TRB3 stimulated canonical TGF-β signalling and induced an activated phenotype in resting fibroblasts. In contrast, knockdown of TRB3 reduced the profibrotic effects of TGF-β and decreased the collagen synthesis. Moreover, siRNA-mediated knockdown of TRB3 exerted potent antifibrotic effects and ameliorated bleomycin as well as constitutively active TGF-β receptor I-induced fibrosis with reduced dermal thickening, decreased hydroxyproline content and impaired myofibroblast differentiation.ConclusionsThe present study characterises TRB3 as a novel profibrotic mediator in SSc. TGF-β induces TRB3, which in turn activates canonical TGF-β/Smad signalling and stimulates the release of collagen, thereby inducing a positive feedback loop that may contribute to aberrant TGF-β signalling in SSc.

scholarly journals Noncoding RNAs as Promising Diagnostic Biomarkers and Therapeutic Targets in Intestinal Fibrosis of Crohn’s Disease: The Path From Bench to Bedside

2020 ◽  
Author(s):  
Long-Yuan Zhou ◽  
Si-Nan Lin ◽  
Florian Rieder ◽  
Min-Hu Chen ◽  
Sheng-Hong Zhang ◽  
...  
Keyword(s):  
Epithelial To Mesenchymal Transition ◽  
Transforming Growth Factor ◽  
Noncoding Rnas ◽  
Transforming Growth Factor Β ◽  
Circular Rnas ◽  
Diagnostic Biomarkers ◽  
Mesenchymal Transition ◽  
Intestinal Fibrosis ◽  
Fibrotic Diseases ◽  
Endothelial To Mesenchymal Transition

Abstract Fibrosis is a major pathway to organ injury and failure, accounting for more than one-third of deaths worldwide. Intestinal fibrosis causes irreversible and serious clinical complications, such as strictures and obstruction, secondary to a complex pathogenesis. Under the stimulation of profibrotic soluble factors, excessive activation of mesenchymal cells causes extracellular matrix deposition via canonical transforming growth factor-β/Smads signaling or other pathways (eg, epithelial-to-mesenchymal transition and endothelial-to-mesenchymal transition) in intestinal fibrogenesis. In recent studies, the importance of noncoding RNAs (ncRNAs) stands out in fibrotic diseases in that ncRNAs exhibit a remarkable variety of biological functions in modulating the aforementioned fibrogenic responses. In this review, we summarize the role of ncRNAs, including the emerging long ncRNAs and circular RNAs, in intestinal fibrogenesis. Notably, the translational potential of ncRNAs as diagnostic biomarkers and therapeutic targets in the management of intestinal fibrosis is discussed based on clinical trials from fibrotic diseases in other organs. The main points of this review include the following: • Characteristics of ncRNAs and mechanisms of intestinal fibrogenesis • Wide participation of ncRNAs (especially the emerging long ncRNAs and circular RNAs) in intestinal fibrosis, including transforming growth factor-β signaling, epithelial-to-mesenchymal transition/endothelial-to-mesenchymal transition, and extracellular matrix remodeling • Translational potential of ncRNAs in the diagnosis and treatment of intestinal fibrosis based on clinical trials from fibrotic diseases in other organs

scholarly journals SARP, a new alternatively spliced protein phosphatase 1 and DNA interacting protein

2007 ◽  
Vol 402 (1) ◽  
pp. 187-196 ◽  
Author(s):  
Gareth J. Browne ◽  
Margarida Fardilha ◽  
Senga K. Oxenham ◽  
Wenjuan Wu ◽  
Nicholas R. Helps ◽  
...  
Keyword(s):  
Protein Phosphatase ◽  
Mammalian Cells ◽  
Leucine Zipper ◽  
Transforming Growth Factor ◽  
Binding Protein ◽  
Transforming Growth Factor Β ◽  
Ankyrin Repeat ◽  
Protein Phosphatase 1 ◽  
Binding Motif ◽  
Alternative Mrna Splicing

PP1 (protein phosphatase 1) is a ubiquitously expressed serine/threonine-specific protein phosphatase whose activity towards different substrates appears to be mediated via binding to specific proteins that play critical regulatory and targeting roles. In the present paper we report the cloning and characterization of a new protein, termed SARP (several ankyrin repeat protein), which is shown to interact with all isoforms of PP1 by a variety of techniques. A region encompassing a consensus PP1-binding motif in SARP (K354VHF357) modulates endogenous SARP–PP1 activity in mammalian cells. This SARP–PP1 interaction motif lies partially within the first ankyrin repeat in contrast with other proteins [53BP2 (p53 binding protein 2), MYPT1/M110/MBS (myosin binding protein of PP1) and TIMAP (transforming growth factor β inhibited, membrane-associated protein)], where a PP1-binding motif precedes the ankyrin repeats. Alternative mRNA splicing produces several isoforms of SARP from a single human gene at locus 11q14. SARP1 and/or SARP2 (92–95 kDa) are ubiquitously expressed in all tissues with high levels in testis and sperm, where they are shown to interact with both PP1γ1 and PP1γ2. SARP3 (65 kDa) is most abundant in brain where SARP isoforms interact with both PP1α and PP1γ1. SARP is highly abundant in the nucleus of mammalian cells, consistent with the putative nuclear localization signal at the N-terminus. The presence of a leucine zipper near the C-terminus of SARP1 and SARP2, and the binding of mammalian DNA to SARP2, suggests that SARP1 and SARP2 may be transcription factors or DNA-associated proteins that modulate gene expression.

Long Noncoding RNA MIAT Modulates the Extracellular Matrix Deposition in Leiomyomas by Sponging MiR-29 Family

Endocrinology ◽  
2021 ◽  
Vol 162 (11) ◽  
Author(s):  
Tsai-Der Chuang ◽  
Derek Quintanilla ◽  
Drake Boos ◽  
Omid Khorram
Keyword(s):  
Extracellular Matrix ◽  
Long Noncoding Rna ◽  
Noncoding Rna ◽  
Collagen Type ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Luciferase Reporter ◽  
Cycle Phase ◽  
Type I ◽  
Matrix Deposition

Abstract The objective of this study was to determine the expression and functional role of a long noncoding RNA (lncRNA) MIAT (myocardial infarction–associated transcript) in leiomyoma pathogenesis. Leiomyoma compared with myometrium (n = 66) expressed significantly more MIAT that was independent of race/ethnicity and menstrual cycle phase but dependent on MED12 (mediator complex subunit 12) mutation status. Leiomyomas bearing the MED12 mutation expressed higher levels of MIAT and lower levels of microRNA 29 family (miR-29a, -b, and -c) compared with MED12 wild-type leiomyomas. Using luciferase reporter activity and RNA immunoprecipitation analysis, MIAT was shown to sponge the miR-29 family. In a 3-dimensional spheroid culture system, transient transfection of MIAT siRNA in leiomyoma smooth muscle cell (LSMC) spheroids resulted in upregulation of miR-29 family and downregulation of miR-29 targets, collagen type I (COL1A1), collagen type III (COL3A1), and TGF-β3 (transforming growth factor β-3). Treatment of LSMC spheroids with TGF-β3 induced COL1A1, COL3A1, and MIAT levels, but repressed miR-29 family expression. Knockdown of MIAT in LSMC spheroids blocked the effects of TGF-β3 on the induction of COL1A1 and COL3A1 expression. Collectively, these results underscore the physiological significance of MIAT in extracellular matrix accumulation in leiomyoma.

scholarly journals Knockdown of Long Noncoding RNA H19 Represses the Progress of Pulmonary Fibrosis through the Transforming Growth Factor β/Smad3 Pathway by Regulating MicroRNA 140

2019 ◽  
Vol 39 (12) ◽  
Author(s):  
Xi Wang ◽  
Zhe Cheng ◽  
Lingling Dai ◽  
Tianci Jiang ◽  
Liuqun Jia ◽  
...  
Keyword(s):  
Growth Factor ◽  
Pulmonary Fibrosis ◽  
Noncoding Rna ◽  
Molecular Mechanisms ◽  
Transforming Growth Factor ◽  
Animal Experiments ◽  
A549 Cells ◽  
Transforming Growth Factor Β ◽  
Tgf Β1

ABSTRACT Long noncoding RNAs (lncRNAs) are involved in various human diseases. Recently, H19 was reported to be upregulated in fibrotic rat lung and play a stimulative role in bleomycin (BLM)-induced pulmonary fibrosis in mice. However, its expression in human fibrotic lung tissues and mechanism of action remain unclear. Here, our observations showed that H19 expression was significantly upregulated and that of microRNA 140 (miR-140) was markedly reduced in pulmonary fibrotic tissues from idiopathic pulmonary fibrosis (IPF) patients and transforming growth factor β1 (TGF-β1)-induced HBE and A549 cells. Moreover, the expression of H19 was negatively correlated with the expression of miR-140 in IPF tissues. H19 knockdown attenuated TGF-β1-induced pulmonary fibrosis in vitro. Furthermore, animal experiments showed that H19 knockdown attenuated BLM-induced pulmonary fibrosis in mice. The study of molecular mechanisms showed that H19 functioned via reduction of miR-140 expression by binding to miR-140. The increase of miR-140 inhibited TGF-β1-induced pulmonary fibrosis, and H19 upregulation diminished the inhibitory effects of miR-140 on TGF-β1-induced pulmonary fibrosis, which was involved in the TGF-β/Smad3 pathway. Taken together, our findings showed that H19 knockdown attenuated pulmonary fibrosis via the regulatory network of lncRNA H19–miR-140–TGF-β/Smad3 signaling, and H19 and miR-140 might represent therapeutic targets and early diagnostic and prognostic biomarkers for patients with pulmonary fibrosis.

Sign in / Sign up

Export Citation Format

Share Document