Constitutively active Notch1 signaling promotes endothelial-mesenchymal transition in a conditional transgenic mouse model

Liu, Ju; Fang, Dong; Jeong, James; Masuda, Takahiro; Lobe, Corrinne G.

doi:10.3892/ijmm.2014.1818

Cited by 33 publications

(25 citation statements)

References 60 publications

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“…Moreover, a TEK-GFP genetic mouse model was applied for a colocalization analysis as the mesenchymal cell marker ACTA2 colocalized with TEK-GFP. The molecular mechanisms involved in the switch from an endothelial phenotype to a mesenchymal status are complicated and controlled by various signaling pathways, such as the WNT, NOTCH and TGFB pathways [53][54][55]. Consistent with a previous study [54], NOTCH1 signaling lies downstream of circHECW2-MIR30D-ATG5 as shown in our current study.…”

Section: Discussionsupporting

confidence: 92%

“…The molecular mechanisms involved in the switch from an endothelial phenotype to a mesenchymal status are complicated and controlled by various signaling pathways, such as the WNT, NOTCH and TGFB pathways [53][54][55]. Consistent with a previous study [54], NOTCH1 signaling lies downstream of circHECW2-MIR30D-ATG5 as shown in our current study. Given that ATG5 contains substantial numbers of acidic residues, a potential glycosylation site, protein kinase C and tyrosine kinase sites [56], further investigation was required to identify the precise mechanism that underlies the activation of the NOTCH1 pathway induced by circHECW2-MIR30D-ATG5.…”

Section: Discussionsupporting

confidence: 92%

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Engagement of circular RNA HECW2 in the nonautophagic role of ATG5 implicated in the endothelial-mesenchymal transition

et al. 2018

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Endothelial-mesenchymal transition (EndoMT) is associated with damage to blood-brain barrier (BBB) integrity. Circular RNAs (circRNAs) are highly expressed in the brain and are involved in brain diseases; however, whether circRNAs regulate the EndoMT in the brain remains unknown. Our study demonstrated that circHECW2 regulated the EndoMT by directly binding to MIR30D, a significantly downregulated miRNA from miRNA profiling, which subsequently caused an increased expression of ATG5. These findings shed new light on the understanding of the noncanonical role of ATG5 in the EndoMT induced by methamphetamine (Meth) or lipopolysaccharide (LPS). The in vivo relevance was confirmed as microinjection of circHecw2 siRNA lentivirus into the mouse hippocampus suppressed the EndoMT induced by LPS. These findings provide novel insights regarding the contribution of circHECW2 to the nonautophagic role of ATG5 in the EndoMT process in the context of drug abuse and the broad range of neuroinflammatory disorders.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionsupporting

confidence: 92%

Engagement of circular RNA HECW2 in the nonautophagic role of ATG5 implicated in the endothelial-mesenchymal transition

et al. 2018

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“…no Zeg-ic-notch1/tie2-cre positive offspring were obtained, and we found that the double transgenic embryos died before e10.5 with defects in vascular development and widespread hemorrhaging. these observations were consistent with our previous studies showing the lethality of Zeg-ic-notch1/tie2-cre embryos with lack of angiogenic remodeling and branching in the yolk sacs and embryonic bodies (24,25). In these IC-Notch1 expressing embryos, the circulation system of hematopoietic cells have been developed before the death of the embryos.…”

Section: Zeg-ic-notch1supporting

confidence: 82%

“…these results contribute to the understanding of the role of notch1 signaling in leukemiagenesis/lymphomagenesis in adults. the homogenous deletion of Notch1 or constitutive activation of Notch1 under Tie2 promoter in mice all induced early embryonic lethality between 9.5-11.5 with a phenotype of disruption of vasculature (24,36). Since Notch1 and Tie2 promoter are also expressed in hematopoietic cells, defects in hematopoietic system might contribute to the phenotype.…”

Section: Ic-notch1 Expression Was Activated In Hematopoietic Cellsmentioning

confidence: 99%

Postnatal Notch1 activation induces T-cell malignancy in conditional and inducible mouse models

Liu

Fang

Fung

et al. 2014

International Journal of Oncology

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Abstract. the notch1 signaling pathway is essential for hematopoietic development. However, the effects of postnatal activation of notch1 signaling on hematopoietic system is not yet fully understood. We previously generated ZEG-IC-Notch1 transgenic mice that have a floxed β-geo/stop signal between a cMV promoter and intracellular domain of notch1 (ic-notch1). constitutively active ic-notch1 is silent until the introduction of cre recombinase. in this study, endothelial/hematopoietic specific expression of IC-Notch1 in double transgenic Zeg-ic-notch1/tie2-cre embryos induced embryonic lethality at e9.5 with defects in vascular system but not in hematopoietic system. Inducible IC-Notch1 expression in adult mice was achieved by using tetracycline regulated cre system. the Zeg-ic-notch1/tie2-tta/tet-o-cre triple transgenic mice survived embryonic development when maintained on tetracycline. Post-natal withdrawal of tetracycline induced expression of IC-Notch1 transgene in hematopoietic cells of adult mice. The triple transgenic mice displayed extensive T-cell infiltration in multiple organs and T-cell malignancy of lymph nodes. in addition, the protein levels of p53 and alternative reading frame (arf) were decreased in lymphoma-like neoplasms from the triple transgenic mice while their mrna expression remained unchanged, suggesting that IC-Notch1 might repress arf-p53 pathway by a post-transcriptional mechanism. this study demonstrated that activation of constitutive notch1 signaling after embryonic development alters adult hematopoiesis and induces t-cell malignancy. Introductionnotch is a family of highly conserved cell-surface receptors that are required in many mammalian developmental processes (1). the interaction of notch receptors and its ligands initiates a cascade of proteolytic cleavages. tnf-α converting enzyme, a metalloprotease, cleaves the extracellular subunit to leave membrane-bound form of the transmembrane subunit of notch receptors. Then a presenilin-associated multiprotein complex with γ-secretase activity recognizes and cleaves a site within the transmembrane domain to release the intracellular domain of notch (ic-notch). ic-notch translocates to the nucleus and converts the transcription factor cBf1/Su(H)/lag1 (cSl) from a repressor to a transcriptional activator (2). the downstream targets of notch/cSl include Hairy-enhancer of split (HeS) and Hes-related protein (HerP/Hey) families, which function as transcriptional repressors suppressing the expression of cell type specific target genes (3).to date, four notch receptors (notch 1-4) and five ligands (δ-like 1, 2 and 4; jagged 1 and 2) have been described in mammals (2). Notch1 is expressed in most embryonic and adult tissues. Notch1 protein has an extracellular domain consisting of multiple egf-like repeats and three cysteine-rich lin12 repeats with heterodimerization (HD) domain, a transmembrane domain and intracellular domain containing a CSL associating motif domain, six ankyrin repeats, nuclear localization signals (nlS), a glutamine-ric...

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“…In recent years, the Notch1 signaling pathway has attracted widespread attention (10)(11)(12)(13)(14)(15)(17)(18)(19)(20)33). However, previous studies in this field have mainly focused on the cellular (10,12,20) and animal levels (11,19,33) and no research has been carried out at the human clinical trial level. In our study, human H9c2 cells from were used to create a model of myocardial injury.…”

Section: Discussionmentioning

confidence: 99%

Protective effects of Notch1 signaling activation against high glucose-induced myocardial cell injury: Analysis of its mechanisms of action

Zhang¹,

Li²,

Zheng³

et al. 2015

International Journal of Molecular Medicine

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Notch1 plays an important role in cardiomyocyte apoptosis and cardiac fibrosis. However, the effects of Notch1 on diabetic cardiomyopathy (DCM) and its mechanisms of action remain unclear. In the present study, we sought to investigate the role of Notch1 in, and its effects on high glucose (HG)‑induced myocardial cell apoptosis and myocardial fibrosis. H9c2 cells exposed to HG were used to establish an in vitro model of myocardial injury. The H9c2 cells were cultured with normal glucose (NG; 5.5 mmol/L‑ NG), and were then epxosed to HG (33 mmol/L‑ HG), a γ‑secretase inhibitor (DAPT), and were transfected with a lentiviral vector containing the Notch1 intracellular domain (N1ICD; lentivirus‑N1ICD). At 72 h following exposure to HG, DAPT or transfection with lentivirus‑N1ICD, myocardial cell viability was assessed using a Cell Counting kit‑8 (CCK‑8) assay. Cell apoptosis was measured using Annexin V/propidium iodide (PI) double staining and flow cytometry. The mRNA expression levels of hairy/enhancer of split‑1 (Hes‑1) and hairy/enhancer-of-split related with YRPW motif‑1 (Hey‑1) were measured by quantitative PCR (qPCR), while the protein expression of N1ICD, Bax, Bcl‑2, transforming growth factor‑β1 (TGF‑β1) and connective tissue growth factor (CTGF), and the levels of phosphorylated (p-)AKT, total (t-)AKT, p‑phosphoinositide 3-kinase (PI3K) and t‑AKT were measured by western blot analysis. Our results revealed that exposure to HG induced apoptosis and upregulated TGF‑β1 and CTGF expression in the H9c2 cardiomyocytes. Furthermore, the Notch1 and PI3K/AKT signaling pathways were activated following transfection with lentivirus‑N1ICD, and this activation enhanced myocardial cell viability, prevented cardiomyocyte apoptosis and decreased TGF‑β1 and CTGF expression. On the whole, our data demonstrate that the overexpression of Notch1 prevents HG‑induced cardiomyocyte apoptosis and decreases CTGF expression in H9c2 cells exposed to HG. Thus, Notch1 may be used to prevent the development of DCM and to inhibit cardiac fibrosis. The findings of our study may prove to be of use in the development of novel therapeutic strategies for DCM.

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Constitutively active Notch1 signaling promotes endothelial-mesenchymal transition in a conditional transgenic mouse model

Cited by 33 publications

References 60 publications

Engagement of circular RNA HECW2 in the nonautophagic role of ATG5 implicated in the endothelial-mesenchymal transition

Engagement of circular RNA HECW2 in the nonautophagic role of ATG5 implicated in the endothelial-mesenchymal transition

Postnatal Notch1 activation induces T-cell malignancy in conditional and inducible mouse models

Protective effects of Notch1 signaling activation against high glucose-induced myocardial cell injury: Analysis of its mechanisms of action

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