Activation of Notch1 signaling in cardiogenic mesoderm induces abnormal heart morphogenesis in mouse

AbstractNotch signaling plays important roles in the regulation of immune cell functioning during the inflammatory response. Activation of the innate immune signaling receptor NLRP3 promotes inflammation in injured tissue. However, it remains unknown whether Jagged1 (JAG1)-mediated myeloid Notch1 signaling regulates NLRP3 function in acute liver injury. Here, we report that myeloid Notch1 signaling regulates the NLRP3-driven inflammatory response in ischemia/reperfusion (IR)-induced liver injury. In a mouse model of liver IR injury, Notch1-proficient (Notch1FL/FL) mice receiving recombinant JAG1 showed a reduction in IR-induced liver injury and increased Notch intracellular domain (NICD) and heat shock transcription factor 1 (HSF1) expression, whereas myeloid-specific Notch1 knockout (Notch1M-KO) aggravated hepatocellular damage even with concomitant JAG1 treatment. Compared to JAG1-treated Notch1FL/FL controls, Notch1M-KO mice showed diminished HSF1 and Snail activity but augmented NLRP3/caspase-1 activity in ischemic liver. The disruption of HSF1 reduced Snail activation and enhanced NLRP3 activation, while the adoptive transfer of HSF1-expressing macrophages to Notch1M-KO mice augmented Snail activation and mitigated IR-triggered liver inflammation. Moreover, the knockdown of Snail in JAG1-treated Notch1FL/FL livers worsened hepatocellular functioning, reduced TRX1 expression and increased TXNIP/NLRP3 expression. Ablation of myeloid Notch1 or Snail increased ASK1 activation and hepatocellular apoptosis, whereas the activation of Snail increased TRX1 expression and reduced TXNIP, NLRP3/caspase-1, and ROS production. Our findings demonstrated that JAG1-mediated myeloid Notch1 signaling promotes HSF1 and Snail activation, which in turn inhibits NLRP3 function and hepatocellular apoptosis leading to the alleviation of IR-induced liver injury. Hence, the Notch1/HSF1/Snail signaling axis represents a novel regulator of and a potential therapeutic target for liver inflammatory injury.

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NOTCH1 signaling regulates the BMP2/DLX-3 directed osteogenic differentiation of dental follicle cells

Biochemical and Biophysical Research Communications ◽

10.1016/j.bbrc.2013.11.120 ◽

2014 ◽

Vol 443 (2) ◽

pp. 500-504 ◽

Cited By ~ 17

Author(s):

Sandra Viale-Bouroncle ◽

Martin Gosau ◽

Christian Morsczeck

Keyword(s):

Osteogenic Differentiation ◽

Follicle Cells ◽

Dental Follicle ◽

Dental Follicle Cells ◽

Notch1 Signaling

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The Impact of Mechanical Forces in Heart Morphogenesis

Circulation Cardiovascular Genetics ◽

10.1161/circgenetics.111.961086 ◽

2012 ◽

Vol 5 (1) ◽

pp. 132-142 ◽

Cited By ~ 47

Author(s):

Javier T. Granados-Riveron ◽

J. David Brook

Keyword(s):

Mechanical Forces ◽

Heart Morphogenesis ◽

The Impact

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Inhibition of Notch1 signaling reduces hepatocyte injury in nonalcoholic fatty liver disease via autophagy

Biochemical and Biophysical Research Communications ◽

10.1016/j.bbrc.2021.02.039 ◽

2021 ◽

Vol 547 ◽

pp. 131-138

Author(s):

Min Zhang ◽

Pengbo Wu ◽

Ming Li ◽

Yitian Guo ◽

Tian Tian ◽

...

Keyword(s):

Liver Disease ◽

Fatty Liver ◽

Nonalcoholic Fatty Liver Disease ◽

Fatty Liver Disease ◽

Nonalcoholic Fatty Liver ◽

Notch1 Signaling ◽

Hepatocyte Injury

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Oncogene APOL1 promotes proliferation and inhibits apoptosis via activating NOTCH1 signaling pathway in pancreatic cancer

Cell Death and Disease ◽

10.1038/s41419-021-03985-1 ◽

2021 ◽

Vol 12 (8) ◽

Author(s):

Jiewei Lin ◽

Zhiwei Xu ◽

Junjie Xie ◽

Xiaxing Deng ◽

Lingxi Jiang ◽

...

Keyword(s):

Pancreatic Cancer ◽

Signaling Pathway ◽

Density Lipoprotein ◽

Human Pancreatic Cancer ◽

Luciferase Reporter ◽

Notch1 Signaling ◽

In Vivo Experiments ◽

Notch1 Signaling Pathway

AbstractAPOL1 encodes a secreted high-density lipoprotein, which has been considered as an aberrantly expressed gene in multiple cancers. Nevertheless, the role of APOL1 in the regulatory mechanisms of pancreatic cancer remains unknown and should be explored. We identified APOL1 was abnormally elevated in human pancreatic cancer tissues compared with that in adjacent tissues and was associated with poor prognosis. The effects of APOL1 in PC cell proliferation, cell cycle, and apoptosis was verified via functional in vitro and in vivo experiments. The results showed that knockdown of APOL1 significantly inhibited the proliferation and promoted apoptosis of pancreatic cancer. In addition, we identified APOL1 could be a regulator of NOTCH1 signaling pathway using bioinformatics tools, qRT-PCR, dual-luciferase reporter assay, and western blotting. In summary, APOL1 could function as an oncogene to promote proliferation and inhibit apoptosis through activating NOTCH1 signaling pathway expression in pancreatic cancer; therefore, it may act as a novel therapeutic target for pancreatic cancer.

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CSIG-13. TRPM7 INDUCES TUMORIGENESIS AND STEMNESS THROUGH NOTCH ACTIVATION IN GLIOMA

Neuro-Oncology ◽

10.1093/neuonc/noaa215.125 ◽

2020 ◽

Vol 22 (Supplement_2) ◽

pp. ii30-ii30

Author(s):

Jingwei Wan ◽

Alyssa Guo ◽

Mingli Liu

Keyword(s):

Notch Signaling ◽

Glioma Cell ◽

Glioma Cells ◽

Inhibitory Effect ◽

Notch Signaling Pathway ◽

Normal Brain ◽

Diffuse Astrocytoma ◽

Notch1 Signaling ◽

Signaling Activation ◽

Proliferation And Invasion

Abstract Our group found that the inhibitory effect of TRPM7 on proliferation and invasion of human glioma cell is mediated by multiple mechanisms. TRPM7 regulates miR-28-5p expression, which suppresses cell proliferation and invasion in glioma cells by targeting Ras-related protein Rap1b. In particular, our group found that TRPM7 channels regulate glioma stem cell (GSC) growth/proliferation through STAT3 and Notch signaling. However, which Notch component(s) is crucial for its activity regulated by TRPM7, and its relationship with other GSC markers, such as CD133 and ALDH1, remain unclear. In the current project, we elucidate the mechanisms of TRMP7’s regulation of Notch signaling pathway that contribute to the development and progression of glioma and maintenance of self-renewal and tumorigenicity of GSC using multiple glioma cell lines (GC) with different molecular subtypes and GSCs derived from the GC lines. 1) We first analyzed TRPM7 expression using the Oncomine database (https://www.oncomine.org) and found that the TRPM7 mRNA expression is significantly increased in anaplastic astrocytoma, diffuse astrocytoma, and GBM patients compared to that in normal brain tissue controls. 2) TRPM7 is expressed in GBM, and its channel activity is correlated with Notch1 activation. Inhibition of TRPM7 downregulates Notch1 signaling, while upregulation of TRPM7 upregulates Notch1 signaling. 3) GSC markers, CD133 and ALDH1, are correlated with TRPM7 in GBM. 4) Targeting TRPM7 suppresses the growth and proliferation of glioma cells through G1/S arrests and apoptosis of glioma cells. 5) Targeting Notch1 suppresses the TRPM7-induced growth and proliferation of glioma cells, as well as the expression of GSC markers CD133 and ALDH1. In summary, TRPM7 is responsible for sustained Notch signaling activation, enhanced expression of GSC markers, and regulation of glioma stemness, which contribute to malignant glioma cell growth and invasion. Notch1 and ligand DII4 are key components that contribute GSC stemness.

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Long non-coding RNA TUG1 knockdown hinders the tumorigenesis of multiple myeloma by regulating the microRNA-34a-5p/NOTCH1 signaling pathway

Open Life Sciences ◽

10.1515/biol-2020-0025 ◽

2020 ◽

Vol 15 (1) ◽

pp. 284-295

Author(s):

Yongtian Zhang ◽

Dandan Zhao ◽

Shumei Li ◽

Meng Xiao ◽

Hongjing Zhou ◽

...

Keyword(s):

Multiple Myeloma ◽

Signaling Pathway ◽

Notch Receptor ◽

Cell Counting ◽

Luciferase Reporter ◽

Notch1 Signaling ◽

Non Coding Rna ◽

Notch1 Signaling Pathway ◽

Long Non Coding Rna

AbstractMultiple myeloma (MM) is a serious health issue in hematological malignancies. Long non-coding RNA taurine-upregulated gene 1 (TUG1) has been reported to be highly expressed in the plasma of MM patients. However, the functions of TUG1 in MM tumorigenesis along with related molecular basis are still undefined. In this study, increased TUG1 and decreased microRNA-34a-5p (miR-34a-5p) levels in MM tissues and cells were measured by the real-time quantitative polymerase reaction assay. The expression of relative proteins was determined by the Western blot assay. TUG1 knockdown suppressed cell viability, induced cell cycle arrest and cell apoptosis in MM cells, as shown by Cell Counting Kit-8 and flow cytometry assays. Bioinformatics analysis, luciferase reporter assay, and RNA pull-down assay indicated that miR-34a-5p was a target of TUG1 and directly bound to notch receptor 1 (NOTCH1), and TUG1 regulated the NOTCH1 expression by targeting miR-34a-5p. The functions of miR-34a-5p were abrogated by TUG1 upregulation. Moreover, TUG1 loss impeded MM xenograft tumor growth in vivo by upregulating miR-34a-5p and downregulating NOTCH1. Furthermore, TUG1 depletion inhibited the expression of Hes-1, Survivin, and Bcl-2 protein in MM cells and xenograft tumors. TUG1 knockdown inhibited MM tumorigenesis by regulating the miR-34a-5p/NOTCH1 signaling pathway in vitro and in vivo, deepening our understanding of the TUG1 function in MM.

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