Differential Regulation of Transforming Growth Factor β Signaling Pathways by Notch in Human Endothelial Cells

Fu, YangXin; Chang, Alex Chia Yu; Chang, Linda; Niessen, Kyle; Eapen, Shawn; Setiadi, Audi; Karsan, Aly

doi:10.1074/jbc.m109.011833

Cited by 104 publications

(100 citation statements)

References 48 publications

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“…Endothelial-specific dnMAML mutants have a severe delay in development, pericardial effusions, and major defects in the vasculature [155]. Additionally, the induction of dnMAML in the endothelium at E8.5 and E9.5 causes a decrease in the number of mesenchymal cells in the AVC cushions [136] and demonstrates that loss of Notch signalling severely impairs cardiac cushion development by blocking EMT.…”

Section: Notch Signalling In Cardiac Valve Developmentmentioning

confidence: 99%

“…As a complex, NICD, RBPJ, and MAML lead to direct activation of Notch target genes ( Figure 2B), such as the hairy enhancer of split (HES) and hairy/ enhancer of split-related with YRPW motif (HEY, also called HESR, CHF, HRT) family proteins [132,133]. Previous work from our group has identified Acta2 (also known as smooth muscle actin, SMA), Snai2, Smad3, and Runx3 as direct Notch target genes in the developing heart [134][135][136][137]. Additional Notch target genes such as c-Myc and cyclin D1 and D3 are reviewed in [138], however, these targets genes have been identified in other systems and not in developing heart and heart valves.…”

Section: Notch Signal Transductionmentioning

confidence: 99%

Section: Synergistic Activation Of Target Genes Via Notch and Smadsmentioning

confidence: 99%

“…Notch activation (via over-expression of NICD or ligand-induced activation) in endothelial cells leads to inhibition of TGFβ-induced Smad1 and Smad2 and subsequently a decrease in expression of their target genes [136]. Interestingly, Notch activation in endothelial cells increases mRNA expression of Smad3, extends the protein half-life of Smad3, and has a role in regulation of specific Smad3 target genes [136]. To further support the effect of Notch on Smad3, a mouse that expresses the pan Notch inhibitor, dnMAML specifically in endothelial cells has reduced total Smad3 protein levels and Smad3 nuclear localization in cardiac cushion cells [136].…”

Section: Synergistic Activation Of Target Genes Via Notch and Smadsmentioning

confidence: 99%

“…Interestingly, Notch activation in endothelial cells increases mRNA expression of Smad3, extends the protein half-life of Smad3, and has a role in regulation of specific Smad3 target genes [136]. To further support the effect of Notch on Smad3, a mouse that expresses the pan Notch inhibitor, dnMAML specifically in endothelial cells has reduced total Smad3 protein levels and Smad3 nuclear localization in cardiac cushion cells [136]. In addition, when Notch activation is coupled with TGFβ stimulation, there is a synergistic effect on Smad3 target genes, Ankrd1 and Hey1.…”

Section: Synergistic Activation Of Target Genes Via Notch and Smadsmentioning

confidence: 99%

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Co-ordinating Notch, BMP, and TGF-β signaling during heart valve development

Garside

Chang

Karsan

et al. 2012

Cell. Mol. Life Sci.

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135

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Congenital heart defects affect approximately 1-5% of human newborns each year and of these cardiac defects, 20-30% are due to heart valve abnormalities. Recent literature indicates that key factors and pathways that regulate valve development are also implicated in congenital heart defects and valve disease. Currently, there are limited options for treatment of valve disease and therefore, having a better understanding of valve development can contribute critical insight into congenital valve defects and disease. There are three major signalling pathways required for early specification and initiation of Endothelial-to-Mesenchymal Transformation (EMT) in the cardiac cushions: BMP, TGFβ, and Notch signalling. BMPs secreted from the myocardium setup the environment for the overlying endocardium to become activated, Notch signalling initiates EMT, and both BMP and TGFβ signalling synergizes with Notch to promote the transition of endothelia to mesenchyme and to promote mesenchymal cell invasiveness. Together, these three essential signalling pathways help to form the cardiac cushions and populate them with mesenchyme and, consequently, set off the cascade of events required to develop mature heart valves. Furthermore, integration and cross-talk between these pathways generate highly stratified and delicate valve leaflets and septa of the heart. Here, we discuss BMP, TGFβ, and Notch signalling pathways during mouse cardiac cushion formation and how they together produce a coordinated EMT response in the developing mouse valves.

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Section: Notch Signalling In Cardiac Valve Developmentmentioning

confidence: 99%

Section: Notch Signal Transductionmentioning

confidence: 99%

Section: Synergistic Activation Of Target Genes Via Notch and Smadsmentioning

confidence: 99%

Section: Synergistic Activation Of Target Genes Via Notch and Smadsmentioning

confidence: 99%

Section: Synergistic Activation Of Target Genes Via Notch and Smadsmentioning

confidence: 99%

See 3 more Smart Citations

Co-ordinating Notch, BMP, and TGF-β signaling during heart valve development

Garside

Chang

Karsan

et al. 2012

Cell. Mol. Life Sci.

Self Cite

135

123

View full text Add to dashboard Cite

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Hypoxia activates the notch signaling pathway in cells of the intervertebral disc: Implications in degenerative disc disease

Hiyama

Skubutyte

Markova

et al. 2011

Arthritis & Rheumatism

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Objective To investigate whether hypoxia regulates Notch signaling, and whether Notch plays a role in intervertebral disc cell proliferation. Methods Reverse transcription–polymerase chain reaction and Western blotting were used to measure expression of Notch signaling components in intervertebral disc tissue from mature rats and from human discs. Transfections were performed to determine the effects of hypoxia and Notch on target gene activity. Results Cells of the nucleus pulposus and annulus fibrosus of rat disc tissue expressed components of the Notch signaling pathway. Expression of Notch-2 was higher than that of the other Notch receptors in both the nucleus pulposus and annulus fibrosus. In both tissues, hypoxia increased Notch1 and Notch4 messenger RNA (mRNA) expression. In the annulus fibrosus, mRNA expression of the Notch ligand Jagged1 was induced by hypoxia, while Jagged2 mRNA expression was highly sensitive to hypoxia in both tissues. A Notch signaling inhibitor, L685458, blocked hypoxic induction of the activity of the Notch-responsive luciferase reporters 12xCSL and CBF1. Expression of the Notch target gene Hes1 was induced by hypoxia, while coexpression with the Notch–intracellular domain increased Hes1 promoter activity. Moreover, inhibition of Notch signaling blocked disc cell proliferation. Analysis of human disc tissue showed that there was increased expression of Notch signaling proteins in degenerated discs. Conclusion In intervertebral disc cells, hypoxia promotes expression of Notch signaling proteins. Notch signaling is an important process in the maintenance of disc cell proliferation, and thus offers a therapeutic target for the restoration of cell numbers during degenerative disc disease.

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Multifaceted TGF‐β signaling, a master regulator: From bench‐to‐bedside, intricacies, and complexities

Ahuja,

Zaheer

2023

Cell Biology International

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Physiological embryogenesis and adult tissue homeostasis are regulated by transforming growth factor‐β (TGF‐β), an evolutionarily conserved family of secreted polypeptide factors, acting in an autocrine and paracrine manner. The role of TGF‐β in inflammation, fibrosis, and cancer is complex and sometimes even contradictory, exhibiting either inhibitory or promoting effects depending on the stage of the disease. Under pathological conditions, especially fibrosis and cancer, overexpressed TGF‐β causes extracellular matrix deposition, epithelial–mesenchymal transition, cancer‐associated fibroblast formation, and/or angiogenesis. In this review article, we have tried to dive deep into the mechanism of action of TGF‐β in inflammation, fibrosis, and carcinogenesis. As TGF‐β and its downstream signaling mechanism are implicated in fibrosis and carcinogenesis blocking this signaling mechanism appears to be a promising avenue. However, targeting TGF‐β carries substantial risk as this pathway is implicated in multiple homeostatic processes and is also known to have tumor‐suppressor functions. There is a need for careful dosing of TGF‐β drugs for therapeutic use and patient selection.

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Differential Regulation of Transforming Growth Factor β Signaling Pathways by Notch in Human Endothelial Cells

Cited by 104 publications

References 48 publications

Co-ordinating Notch, BMP, and TGF-β signaling during heart valve development

Co-ordinating Notch, BMP, and TGF-β signaling during heart valve development

Hypoxia activates the notch signaling pathway in cells of the intervertebral disc: Implications in degenerative disc disease

Multifaceted TGF‐β signaling, a master regulator: From bench‐to‐bedside, intricacies, and complexities

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