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 Leukemia cells remodel marrow adipocytes via TRPV4-dependent lipolysis

Haematologica ◽  
2019 ◽  
Vol 105 (11) ◽  
pp. 2572-2583
Author(s):  
Shaoxin Yang ◽  
Wei Lu ◽  
Chong Zhao ◽  
Yuanmei Zhai ◽  
Yanyu Wei ◽  
...  
Keyword(s):  
Transient Receptor Potential ◽  
Transforming Growth Factor ◽  
Critical Role ◽  
Receptor Potential ◽  
Transforming Growth Factor Β ◽  
Leukemia Cells ◽  
Transient Receptor Potential Vanilloid ◽  
Transient Receptor ◽  
Novel Strategy ◽  
And Function

Remodeling of adipocyte morphology and function plays a critical role in prostate cancer development. We previously reported that leukemia cells secrete growth differentiation factor 15 (GDF15)，which remodels the residual bone marrow (BM) adipocytes into small adipocytes and is associated with a poor prognosis in acute myeloid leukemia (AML) patients. However, little is known about how GDF15 drives BM adipocyte remodeling. In this study, we examined the role of the transient receptor potential vanilloid (TRPV) channels in the remodeling of BM adipocytes exposed to GDF15. We found that TRPV4 negatively regulated GDF15-induced remodeling of BM adipocytes. Furthermore, transforming growth factor-β type II receptor (TGFβRII) was identified as the main receptor for GDF15 on BM adipocytes. PI3K inhibitor treatment reduced GDF15-induced pAKT, identifying PI3K/AKT as the downstream stress response pathway. Subsequently, GDF15 reduced the expression of the transcription factor Forkhead box C1 (FOXC1) in BM adipocytes subjected to RNA-seq screening and Western blot analyse. Moreover, it was also confirmed that FOXC1 combined with the TRPV4 promoter by the Chip-qPCR experiments, which suggests that FOXC1 mediates GDF15 regulation of TRPV4. In addition, an AML mouse model exhibited smaller BM adipocytes, whereas the TRPV4 activator 4α-phorbol 12,13-didecanoate (4αPDD) partly rescued this process and increased survival. In conclusion, TRPV4 plays a critical role in BM adipocyte remodeling induced by leukemia cells, suggesting that targeting TRPV4 may constitute a novel strategy for AML therapy.

Transforming growth factor-β-regulated expression of genes in macrophages implicated in the control of cholesterol homoeostasis

2006 ◽  
Vol 34 (6) ◽  
pp. 1141-1144 ◽  
Author(s):  
D.P. Ramji ◽  
N.N. Singh ◽  
P. Foka ◽  
S.A. Irvine ◽  
K. Arnaoutakis
Keyword(s):  
Growth Factor ◽  
Molecular Mechanisms ◽  
Transforming Growth Factor ◽  
Inflammatory Responses ◽  
Critical Role ◽  
Transforming Growth Factor Β ◽  
Crucial Importance ◽  
Expression Of Genes ◽  
Regulated Expression ◽  
Key Genes

The regulation of macrophage cholesterol homoeostasis is of crucial importance in the pathogenesis of atherosclerosis, an underlying cause of heart attack and stroke. Several recent studies have revealed a critical role for the cytokine TGF-β (transforming growth factor-β), a key regulator of the immune and inflammatory responses, in atherogenesis. We discuss here the TGF-β signalling pathway and its role in this disease along with the outcome of our recent studies on the action of the cytokine on the expression of key genes implicated in the uptake or efflux of cholesterol by macrophages and the molecular mechanisms underlying such regulation.

scholarly journals TGF-β Signaling: From Tissue Fibrosis to Tumor Microenvironment

2021 ◽  
Vol 22 (14) ◽  
pp. 7575
Author(s):  
Jeff Yat-Fai Chung ◽  
Max Kam-Kwan Chan ◽  
Jane Siu-Fan Li ◽  
Alex Siu-Wing Chan ◽  
Philip Chiu-Tsun Tang ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Transforming Growth Factor ◽  
Inflammatory Diseases ◽  
Critical Role ◽  
Transforming Growth Factor Β ◽  
Matrix Proteins ◽  
Critical Pathway ◽  
Tissue Fibrosis ◽  
Proliferation And Apoptosis ◽  
Working Mechanisms

Transforming growth factor-β (TGF-β) signaling triggers diverse biological actions in inflammatory diseases. In tissue fibrosis, it acts as a key pathogenic regulator for promoting immunoregulation via controlling the activation, proliferation, and apoptosis of immunocytes. In cancer, it plays a critical role in tumor microenvironment (TME) for accelerating invasion, metastasis, angiogenesis, and immunosuppression. Increasing evidence suggest a pleiotropic nature of TGF-β signaling as a critical pathway for generating fibrotic TME, which contains numerous cancer-associated fibroblasts (CAFs), extracellular matrix proteins, and remodeling enzymes. Its pathogenic roles and working mechanisms in tumorigenesis are still largely unclear. Importantly, recent studies successfully demonstrated the clinical implications of fibrotic TME in cancer. This review systematically summarized the latest updates and discoveries of TGF-β signaling in the fibrotic TME.

scholarly journals TAK1: a potent tumour necrosis factor inhibitor for the treatment of inflammatory diseases

Open Biology ◽  
2020 ◽  
Vol 10 (9) ◽  
pp. 200099
Author(s):  
Juliane Totzke ◽  
Scott A. Scarneo ◽  
Kelly W. Yang ◽  
Timothy A. J. Haystead
Keyword(s):  
Tumour Necrosis Factor ◽  
Tumour Necrosis ◽  
Transforming Growth Factor ◽  
Inflammatory Diseases ◽  
Critical Role ◽  
Transforming Growth Factor Β ◽  
Factor Inhibitor ◽  
Irritable Bowel ◽  
Inflammatory Signalling ◽  
Necrosis Factor

Aberrant tumour necrosis factor (TNF) signalling is a hallmark of many inflammatory diseases including rheumatoid arthritis (RA), irritable bowel disease and lupus. Maladaptive TNF signalling can lead to hyper active downstream nuclear factor (NF)-κβ signalling in turn amplifying a cell's inflammatory response and exacerbating disease. Within the TNF intracellular inflammatory signalling cascade, transforming growth factor-β-activated kinase 1 (TAK1) has been shown to play a critical role in mediating signal transduction and downstream NF-κβ activation. Owing to its role in TNF inflammatory signalling, TAK1 has become a potential therapeutic target for the treatment of inflammatory diseases such as RA. This review highlights the current development of targeting the TNF-TAK1 signalling axis as a novel therapeutic strategy for the treatment of inflammatory diseases.

scholarly journals Molecular Mechanisms of Epithelial to Mesenchymal Transition Regulated by ERK5 Signaling

Biomolecules ◽  
2021 ◽  
Vol 11 (2) ◽  
pp. 183
Author(s):  
Akshita B. Bhatt ◽  
Saloni Patel ◽  
Margarite D. Matossian ◽  
Deniz A. Ucar ◽  
Lucio Miele ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Cancer Progression ◽  
Cell Invasion ◽  
Molecular Mechanisms ◽  
Epithelial To Mesenchymal Transition ◽  
Transforming Growth Factor ◽  
Critical Role ◽  
Transforming Growth Factor Β ◽  
Mitogen Activated Protein Kinase ◽  
Mesenchymal Transition

Extracellular signal-regulated kinase (ERK5) is an essential regulator of cancer progression, tumor relapse, and poor patient survival. Epithelial to mesenchymal transition (EMT) is a complex oncogenic process, which drives cell invasion, stemness, and metastases. Activators of ERK5, including mitogen-activated protein kinase 5 (MEK5), tumor necrosis factor α (TNF-α), and transforming growth factor-β (TGF-β), are known to induce EMT and metastases in breast, lung, colorectal, and other cancers. Several downstream targets of the ERK5 pathway, such as myocyte-specific enhancer factor 2c (MEF2C), activator protein-1 (AP-1), focal adhesion kinase (FAK), and c-Myc, play a critical role in the regulation of EMT transcription factors SNAIL, SLUG, and β-catenin. Moreover, ERK5 activation increases the release of extracellular matrix metalloproteinases (MMPs), facilitating breakdown of the extracellular matrix (ECM) and local tumor invasion. Targeting the ERK5 signaling pathway using small molecule inhibitors, microRNAs, and knockdown approaches decreases EMT, cell invasion, and metastases via several mechanisms. The focus of the current review is to highlight the mechanisms which are known to mediate cancer EMT via ERK5 signaling. Several therapeutic approaches that can be undertaken to target the ERK5 pathway and inhibit or reverse EMT and metastases are discussed.

SnoN as a novel negative regulator of TGF-β/Smad signaling: a target for tailoring organ fibrosis

2015 ◽  
Vol 308 (2) ◽  
pp. H75-H82 ◽  
Author(s):  
Matthew R. Zeglinski ◽  
Mark Hnatowich ◽  
Davinder S. Jassal ◽  
Ian M. C. Dixon
Keyword(s):  
Transforming Growth Factor ◽  
Tissue Injury ◽  
Transforming Growth Factor Β ◽  
Negative Regulator ◽  
Matricellular Protein ◽  
Matrix Remodeling ◽  
Structural Support ◽  
The Matrix ◽  
Protein Components ◽  
And Function

Remodeling of the extracellular matrix is beneficial during the acute wound healing stage following tissue injury. In the short term, resident fibroblasts and myofibroblasts regulate the matrix remodeling process through production of matricellular protein components that provide structural support to the damaged tissue. This process is largely governed by the transforming growth factor-β1 (TGF-β1) pathway, a critical mediator of the remodeling process. In the long term, chronic activation of the TGF-β1 pathway promotes excessive synthesis and deposition of matrix proteins, including fibrillar collagens, which ultimately leads to organ failure. SnoN (and its alternatively-spliced isoforms SnoN2, SnoA, and SnoI) is one of four members of a family of negative regulators of TGF-β1 signaling that includes Ski and functional Smad-suppressing elements on chromosomes 15 and 18. SnoN has been shown to be structurally and functionally similar to Ski and has been demonstrated to directly interact with Ski to abrogate gene expression. Despite this, little progress has been made in delineating a specific role for SnoN in the regulation of myofibroblast phenotype and function. This review outlines the current body of knowledge of what we refer to as the “Ski-Sno superfamily,” with a focus on the structural and functional importance of SnoN in mediating the fibrotic response by myofibroblasts following tissue injury.

scholarly journals Regulation of Renal Fibrosis by Macrophage Polarization

2015 ◽  
Vol 35 (3) ◽  
pp. 1062-1069 ◽  
Author(s):  
Bixia Pan ◽  
Guohui Liu ◽  
Zongpei Jiang ◽  
Dongwen Zheng
Keyword(s):  
Renal Injury ◽  
Renal Fibrosis ◽  
Molecular Mechanisms ◽  
Epithelial To Mesenchymal Transition ◽  
Transforming Growth Factor ◽  
Macrophage Polarization ◽  
Critical Role ◽  
Transforming Growth Factor Β ◽  
M2 Macrophages ◽  
Mesenchymal Transition

Background/Aims: Since renal fibrosis always predisposes end-stage renal disease, elucidation of the molecular mechanisms that underlie the progression of renal fibrosis may substantially improve the understanding and treatment for renal failure. Previous studies have highlighted an important counteraction between transforming growth factor β 1 (TGFβ1) and bone morphogenic protein 7 (BMP7) in the epithelial-to-mesenchymal transition (EMT) of renal tubular epithelial cells during chronic renal injury. Macrophages are also believed to play a critical role in renal fibrosis. However, the relationship between macrophages and EMT is unknown. Methods: Here, we used a mouse unilateral ureteral obstruction (UUO) model to address to these questions, and analyzed macrophage and its subpopulations purified by flow cytometry. Results: We found that the recruited macrophages are polarized to a M2 subtype after renal injury. M2 macrophages released high levels TGFβ1 to suppress BMP7 to enhance EMT-induced renal fibrosis. Depletion of M2 macrophages, but not of M1 macrophages, specifically inhibited EMT, and subsequently the renal fibrosis. Adoptive transplantation of M2 macrophages deteriorated renal fibrosis. Conclusion: Thus, our study highlights M2 macrophages as a critical target for treating renal fibrosis.

Smad7: not only a regulator, but also a cross-talk mediator of TGF-β signalling

2011 ◽  
Vol 434 (1) ◽  
pp. 1-10 ◽  
Author(s):  
Xiaohua Yan ◽  
Ye-Guang Chen
Keyword(s):  
Cross Talk ◽  
Transforming Growth Factor ◽  
Inflammatory Diseases ◽  
Transforming Growth Factor Β ◽  
Negative Regulator ◽  
Cancer Tissue ◽  
Altered Expression ◽  
Cellular Processes ◽  
Smad Proteins ◽  
Membrane Bound

TGF-β (transforming growth factor-β) is a pleiotropic cytokine regulating diverse cellular processes. It signals through membrane-bound receptors, downstream Smad proteins and/or other signalling mediators. Smad7 has been well established to be a key negative regulator of TGF-β signalling. It antagonizes TGF-β signalling through multiple mechanisms in the cytoplasm and in the nucleus. Smad7 can be transcriptionally induced by TGF-β and other growth factors and serves as an important cross-talk mediator of the TGF-β signalling pathway with other signalling pathways. Accordingly, it plays pivotal roles in embryonic development and adult homoeostasis, and altered expression of Smad7 is often associated with human diseases, such as cancer, tissue fibrosis and inflammatory diseases.

scholarly journals Actin Cytoskeleton and Regulation of TGFβ Signaling: Exploring Their Links

Biomolecules ◽  
2021 ◽  
Vol 11 (2) ◽  
pp. 336
Author(s):  
Roberta Melchionna ◽  
Paola Trono ◽  
Annalisa Tocci ◽  
Paola Nisticò
Keyword(s):  
Cancer Progression ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Tissue Homeostasis ◽  
Actin Dynamics ◽  
Human Tissues ◽  
Cellular Functions ◽  
Tgfβ Signaling ◽  
Physical Mechanisms ◽  
And Function

Human tissues, to maintain their architecture and function, respond to injuries by activating intricate biochemical and physical mechanisms that regulates intercellular communication crucial in maintaining tissue homeostasis. Coordination of the communication occurs through the activity of different actin cytoskeletal regulators, physically connected to extracellular matrix through integrins, generating a platform of biochemical and biomechanical signaling that is deregulated in cancer. Among the major pathways, a controller of cellular functions is the cytokine transforming growth factor β (TGFβ), which remains a complex and central signaling network still to be interpreted and explained in cancer progression. Here, we discuss the link between actin dynamics and TGFβ signaling with the aim of exploring their aberrant interaction in cancer.

scholarly journals Mechanosensation and Mechanotransduction by Lymphatic Endothelial Cells Act as Important Regulators of Lymphatic Development and Function

2021 ◽  
Vol 22 (8) ◽  
pp. 3955
Author(s):  
László Bálint ◽  
Zoltán Jakus
Keyword(s):  
Endothelial Cells ◽  
Endothelial Cell ◽  
Cell Fate ◽  
Molecular Mechanisms ◽  
Critical Role ◽  
Mechanical Forces ◽  
Lymphatic Endothelial Cells ◽  
Lymphatic Development ◽  
And Function ◽  
The Impact

Our understanding of the function and development of the lymphatic system is expanding rapidly due to the identification of specific molecular markers and the availability of novel genetic approaches. In connection, it has been demonstrated that mechanical forces contribute to the endothelial cell fate commitment and play a critical role in influencing lymphatic endothelial cell shape and alignment by promoting sprouting, development, maturation of the lymphatic network, and coordinating lymphatic valve morphogenesis and the stabilization of lymphatic valves. However, the mechanosignaling and mechanotransduction pathways involved in these processes are poorly understood. Here, we provide an overview of the impact of mechanical forces on lymphatics and summarize the current understanding of the molecular mechanisms involved in the mechanosensation and mechanotransduction by lymphatic endothelial cells. We also discuss how these mechanosensitive pathways affect endothelial cell fate and regulate lymphatic development and function. A better understanding of these mechanisms may provide a deeper insight into the pathophysiology of various diseases associated with impaired lymphatic function, such as lymphedema and may eventually lead to the discovery of novel therapeutic targets for these conditions.

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