pVHL-mediated SMAD3 degradation suppresses TGF-β signaling

2021 ◽  
Vol 221 (1) ◽  
Author(s):  
Jun Zhou ◽  
Yasamin Dabiri ◽  
Rodrigo A. Gama-Brambila ◽  
Shahrouz Ghafoory ◽  
Mukaddes Altinbay ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Tissue Homeostasis ◽  
Wing Development ◽  
Dynamic Regulation ◽  
Drosophila Wing ◽  
Wing Growth ◽  
Expression And Activity

Transforming growth factor β (TGF-β) signaling plays a fundamental role in metazoan development and tissue homeostasis. However, the molecular mechanisms concerning the ubiquitin-related dynamic regulation of TGF-β signaling are not thoroughly understood. Using a combination of proteomics and an siRNA screen, we identify pVHL as an E3 ligase for SMAD3 ubiquitination. We show that pVHL directly interacts with conserved lysine and proline residues in the MH2 domain of SMAD3, triggering degradation. As a result, the level of pVHL expression negatively correlates with the expression and activity of SMAD3 in cells, Drosophila wing, and patient tissues. In Drosophila, loss of pVHL leads to the up-regulation of TGF-β targets visible in a downward wing blade phenotype, which is rescued by inhibition of SMAD activity. Drosophila pVHL expression exhibited ectopic veinlets and reduced wing growth in a similar manner as upon loss of TGF-β/SMAD signaling. Thus, our study demonstrates a conserved role of pVHL in the regulation of TGF-β/SMAD3 signaling in human cells and Drosophila wing development.

scholarly journals The Potential Association between the Risk of Post-Surgical Adhesion and the Activated Local Angiotensin II Type 1 Receptors: Need for Novel Treatment Strategies

2021 ◽  
pp. 1-8
Author(s):  
Mahmood Tavakkoli ◽  
Saeed Aali ◽  
Borzoo Khaledifar ◽  
Gordon A. Ferns ◽  
Majid Khazaei ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Molecular Mechanisms ◽  
Transforming Growth Factor ◽  
Therapeutic Potential ◽  
Angiotensin Receptor Blockers ◽  
Surgical Techniques ◽  
Treatment Strategies ◽  
Transforming Growth Factor Β

<b><i>Background:</i></b> Post-surgical adhesion bands (PSABs) are a common complication after abdominal or pelvic surgeries for different reasons like cancer treatment. Despite improvements in surgical techniques and the administration of drugs or the use of physical barriers, there has only been limited improvement in the frequency of postoperative adhesions. Complications of PSAB are pain, infertility, intestinal obstruction, and increased mortality. The most important molecular mechanisms for the development of PSAB are inflammatory response, oxidative stress, and overexpression of pro-fibrotic molecules such as transforming growth factor β. However, questions remain about the pathogenesis of this problem, for example, the causes for individual differences or why certain tissue sites are more prone to post-surgical adhesions. <b><i>Summary:</i></b> Addressing the pathological causes of PSAB, the potential role of local angiotensin II/angiotensin II type 1 receptors (AngII/AT1R), may help to prevent this problem. <b><i>Key Message:</i></b> The objective of this article was to explore the role of the AngII/AT1R axis potential to induce PSAB and the therapeutic potential of angiotensin receptor blockers in the prevention and treatment of PSAB.

scholarly journals The Dual Role of STAT1 in Ovarian Cancer: Insight Into Molecular Mechanisms and Application Potentials

2021 ◽  
Vol 9 ◽  
Author(s):  
Xin Li ◽  
Fanchen Wang ◽  
Xiaolin Xu ◽  
Jinguo Zhang ◽  
Guoxiong Xu
Keyword(s):  
Ovarian Cancer ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
Transforming Growth Factor ◽  
Early Stage ◽  
Transforming Growth Factor Β ◽  
Janus Kinase ◽  
Atypical Symptoms ◽  
Stat1 Signaling

The signal transducer and activator of transcription 1 (STAT1) is a transducer protein and acts as a transcription factor but its role in ovarian cancer (OC) is not completely understood. Practically, there are two-faced effects of STAT1 on tumorigenesis in different kinds of cancers. Existing evidence reveals that STAT1 has both tumor-suppressing and tumor-promoting functions involved in angiogenesis, cell proliferation, migration, invasion, apoptosis, drug resistance, stemness, and immune responses mainly through interacting and regulating target genes at multiple levels. The canonical STAT1 signaling pathway shows that STAT1 is phosphorylated and activated by the receptor-activated kinases such as Janus kinase in response to interferon stimulation. The STAT1 signaling can also be crosstalk with other signaling such as transforming growth factor-β signaling involved in cancer cell behavior. OC is often diagnosed at an advanced stage due to symptomless or atypical symptoms and the lack of effective detection at an early stage. Furthermore, patients with OC often develop chemoresistance and recurrence. This review focuses on the multi-faced role of STAT1 and highlights the molecular mechanisms and biological functions of STAT1 in OC.

scholarly journals Knockdown of Latent Transforming Growth Factor-β (TGF-β)-Binding Protein 2 (LTBP2) Inhibits Invasion and Tumorigenesis in Thyroid Carcinoma Cells

2017 ◽  
Vol 25 (4) ◽  
pp. 503-510 ◽  
Author(s):  
Fuqiang Wan ◽  
Li Peng ◽  
ChaoYu Zhu ◽  
XinFa Zhang ◽  
FangWen Chen ◽  
...  
Keyword(s):  
Growth Factor ◽  
Thyroid Carcinoma ◽  
Molecular Mechanisms ◽  
Transforming Growth Factor ◽  
Binding Protein ◽  
Transforming Growth Factor Β ◽  
Vital Role ◽  
Carcinoma Cells ◽  
Human Thyroid

Latent transforming growth factor-β (TGF-β)-binding protein 2 (LTBP2) is one of four proteins in the LTBP family of proteins (LTBP1‐4) and was shown to play a vital role in tumorigenesis. However, little is known regarding the functional role of LTBP2 in thyroid carcinoma. Therefore, the current study aimed to evaluate the effect of LTBP2 expression on the proliferation, invasion, and tumorigenesis in thyroid carcinoma cells and to explore the molecular mechanism of LTBP2 in tumor progression. Our results showed that the expression of LTBP2 is upregulated in human thyroid carcinoma and cell lines. Knockdown of LTBP2 inhibits the proliferation, invasion, and EMT phenotype in thyroid carcinoma cells. Furthermore, knockdown of LTBP2 attenuates thyroid carcinoma growth in nude mice. Finally, knockdown of LTBP2 inhibits activation of the PI3K/Akt pathway in thyroid carcinoma cells. In summary, the present study has provided further evidence that knockdown of LTBP2 inhibits invasion and tumorigenesis in thyroid carcinoma cells. Our findings may help to further elucidate the molecular mechanisms underlying thyroid carcinoma progression and provide candidate targets for the prevention and treatment of thyroid carcinoma.

scholarly journals Possible role of transforming growth factor β as a marker cytokine of type 3 T-helpers in atopic dermatitis pathogenesis

2004 ◽  
Vol 3 (3) ◽  
pp. 27-31
Author(s):  
N. A. Pronina ◽  
V. S. Sviridova ◽  
A. A. Denisov ◽  
V. V. Klimov ◽  
Ye. N. Kologrivova
Keyword(s):  
Atopic Dermatitis ◽  
Biological Activity ◽  
Growth Factor ◽  
Molecular Mechanisms ◽  
Transforming Growth Factor ◽  
Allergic Inflammation ◽  
Transforming Growth Factor Β ◽  
Cell Populations ◽  
Type 3

The role of transforming growth factor β (TGF-β) in atopic dermatitis pathogenesis is discussed basing on the analysis of existing data of cellular and molecular mechanisms of allergic inflammation. Up-to date data of the main T-helper (T-h) lymphocyte subpopulations including Tx1, Tx2, Tx3 has been presented. Functions of regulatory T-cell populations and produced cytokines have been described. The main attention has been accented on the TGF-β structure and biological activity as a main Tx3 cytokine. The current information of TGF-β influence on different cell populations and its biological activity realization mechanism is thoroughly discussed. Information relating to the mechanism of cytokine regulation during atopic dermatitis has been summarized. A deep analysis of possible participation of TGF-β in disbalance formation on Tx1 and Tx2 levels, in disturbances of histological derma structure and allergic inflammation timing has been made.

scholarly journals Role of Endoglin (CD105) in the Progression of Hepatocellular Carcinoma and Anti-Angiogenic Therapy

2018 ◽  
Vol 19 (12) ◽  
pp. 3887 ◽  
Author(s):  
Aldona Kasprzak ◽  
Agnieszka Adamek
Keyword(s):  
Hepatocellular Carcinoma ◽  
Molecular Mechanisms ◽  
Transforming Growth Factor ◽  
Primary Liver Cancer ◽  
Venous Blood ◽  
Transforming Growth Factor Β ◽  
Current Data ◽  
Solid Tumours ◽  
Angiogenic Therapy

The liver is perfused by both arterial and venous blood, with a resulting abnormal microenvironment selecting for more-aggressive malignancies. Hepatocellular carcinoma (HCC) is the most frequent primary liver cancer, the sixth most common cancer globally, and the third leading cause of cancer-related mortality worldwide. HCC is characterized by its hypervascularization. Improving the efficiency of anti-angiogenic treatment and mitigation of anti-angiogenic drug resistance are the top priorities in the development of non-surgical HCC therapies. Endoglin (CD105), a transmembrane glycoprotein, is one of the transforming growth factor β (TGF-β) co-receptors. Involvement of that protein in angiogenesis of solid tumours is well documented. Endoglin is a marker of activated endothelial cells (ECs), and is preferentially expressed in the angiogenic endothelium of solid tumours, including HCC. HCC is associated with changes in CD105-positive ECs within and around the tumour. The large spectrum of endoglin effects in the liver is cell-type- and HCC- stage-specific. High expression of endoglin in non-tumour tissue suggests that this microenvironment might play an especially important role in the progression of HCC. Evaluation of tissue expression, as well as serum concentrations of this glycoprotein in HCC, tends to confirm its role as an important biomarker in HCC diagnosis and prognosis. The role of endoglin in liver fibrosis and HCC progression also makes it an attractive therapeutic target. Despite these facts, the exact molecular mechanisms of endoglin functioning in hepatocarcinogenesis are still poorly understood. This review summarizes the current data concerning the role and signalling pathways of endoglin in hepatocellular carcinoma development and progression, and provides an overview of the strategies available for a specific targeting of CD105 in anti-angiogenic therapy in HCC.

Abstract 544: Meox1, a Novel Regulator in Tgf-ß-induced Smooth Muscle Cell Differentiation

2013 ◽  
Vol 33 (suppl_1) ◽  
Author(s):  
Kun Dong ◽  
Amanda Hsu ◽  
Shiyou Chen
Keyword(s):  
Smooth Muscle ◽  
Smooth Muscle Cell ◽  
Muscle Cell ◽  
Molecular Mechanisms ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Smooth Muscle Cell Differentiation ◽  
Early Markers ◽  
Vasculogenesis And Angiogenesis

Smooth muscle cell (SMC) differentiation is an important process during vasculogenesis and angiogenesis. It is well known that alterations of VSMC phenotype play a role in the progression of several cardiovascular disorders including atherosclerosis, hypertension, and restenosis. However, the molecular mechanisms controlling the differentiation and development of VSMC are largely unknown. Mesenchyme homeobox 1 (MEOX1) is expressed in the early developing somite and derivatives during embryogenesis. Somite has been shown to be one of the origins or progenitors for SMC. Therefore, in this study, we studied the role of MEOX1 in SMC differentiation. We found that transforming growth factor-β (TGF-β) induces MEOX1 expression in the initial phase of SMC differentiation of pluripotent mesenchymal C3H10T1/2 cells. MEOX1 expression appears to be mediated by both PI3 kinase and Smad3 signaling pathways because blockade of these two pathways by specific inhibitors leads to a decreased expression of MEOX1 and SMC markers. Importantly, knockdown of MEOX1 by specific shRNA suppresses TGF-β-induced expression of SMC early markers including SM22α and calponin. MEOX1 overexpression, on the other hand, increases SMC marker expression. These results indicate that MEOX1 is a novel regulator for TGF-β-induced SMC differentiation.

scholarly journals The Role of TGF-β Signaling Pathways in Cancer and Its Potential as a Therapeutic Target

2021 ◽  
Vol 2021 ◽  
pp. 1-16
Author(s):  
Yun Yang ◽  
Wen-Long Ye ◽  
Ruo-Nan Zhang ◽  
Xiao-Shun He ◽  
Jing-Ru Wang ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Molecular Mechanisms ◽  
Transforming Growth Factor ◽  
Immune Escape ◽  
Therapeutic Potential ◽  
Malignant Tumors ◽  
Transforming Growth Factor Β ◽  
Antitumor Effects ◽  
Downstream Signaling

The transforming growth factor-β (TGF-β) signaling pathway mediates various biological functions, and its dysregulation is closely related to the occurrence of malignant tumors. However, the role of TGF-β signaling in tumorigenesis and development is complex and contradictory. On the one hand, TGF-β signaling can exert antitumor effects by inhibiting proliferation or inducing apoptosis of cancer cells. On the other hand, TGF-β signaling may mediate oncogene effects by promoting metastasis, angiogenesis, and immune escape. This review summarizes the recent findings on molecular mechanisms of TGF-β signaling. Specifically, this review evaluates TGF-β′s therapeutic potential as a target by the following perspectives: ligands, receptors, and downstream signaling. We hope this review can trigger new ideas to improve the current clinical strategies to treat tumors related to the TGF-β signaling pathway.

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 LncRNA SNHG16 promotes pulmonary fibrosis by targeting miR-455-3p to regulate the Notch2 pathway

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Panpan Liu ◽  
Lei Zhao ◽  
Yuxia Gu ◽  
Meilan Zhang ◽  
Hongchang Gao ◽  
...  
Keyword(s):  
Pulmonary Fibrosis ◽  
Lung Fibrosis ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Interstitial Lung Diseases ◽  
Luciferase Reporter ◽  
Qrt Pcr ◽  
Rna Immunoprecipitation ◽  
And Migration

Abstract Background Idiopathic pulmonary fibrosis (IPF) is the most common interstitial lung diseases with a poor prognosis. Long non-coding RNAs (lncRNAs) have been reported to be involved in IPF in several studies. However, the role of lncRNA SNHG16 in IPF is largely unknown. Methods Firstly, experimental pulmonary fibrosis model was established by using bleomycin (BML). Histology and Western blotting assays were used to determine the different stages of fibrosis and expression of several fibrosis biomarkers. The expression of SNHG16 was detected by quantitative real-time polymerase chain reaction (qRT‐PCR). EdU staining and wound-healing assay were utilized to analyze proliferation and migration of lung fibroblast cells. Molecular mechanism of SNHG16 was explored by bioinformatics, dual-luciferase reporter assay, RNA immunoprecipitation assay (RIP), and qRT-PCR. Results The expression of SNHG16 was significantly up-regulated in bleomycin-(BLM) induced lung fibrosis and transforming growth factor-β (TGF-β)-induced fibroblast. Knockdown of SNHG16 could attenuate fibrogenesis. Mechanistically, SNHG16 was able to bind and regulate the expression of miR-455-3p. Moreover, SNHG16 also regulated the expression of Notch2 by targeting miR-455-3p. Finally, SNHG16 could promote fibrogenesis by regulating the expression of Notch2. Conclusion Taken together, our study demonstrated that SNHG16 promoted pulmonary fibrosis by targeting miR-455-3p to regulate the Notch2 pathway. These findings might provide a novel insight into pathologic process of lung fibrosis and may provide prevention strategies in the future.

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