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Notch1 dose modulates endothelial gene expression

ABSTRACT: Purpose: To use RNA-Seq analysis of endothelial cell in various Notch1 alllels in order to determine transcrptional differencesas a consequence of Notch dose. Methods: Using a FACS sorting we generated high-throughput RNA-SEQ data of endothelials in various Notch1 alleles during development Results: Notch1 dose can alter gene expression in a subset of endothelial genes RNA-Seq was performed on endothelial cells isolated at e9.5 from embryos with various Notch1 alleles including N1+/+, N1+/-, N1+/vg, N112/vg, N112/-

ORGANISM(S): Mus musculus

SUBMITTER: Raphael Kopan

PROVIDER: E-GEOD-69276 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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The intracellular domains of Notch1 and Notch2 are functionally equivalent during development and carcinogenesis.

Liu Zhenyi Z Brunskill Eric E Varnum-Finney Barbara B Zhang Chi C Zhang Andrew A Jay Patrick Y PY Bernstein Irv I Morimoto Mitsuru M Kopan Raphael R

Development (Cambridge, England) 20150610 14

Although Notch1 and Notch2 are closely related paralogs and function through the same canonical signaling pathway, they contribute to different outcomes in some cell and disease contexts. To understand the basis for these differences, we examined in detail mice in which the Notch intracellular domains (N1ICD and N2ICD) were swapped. Our data indicate that strength (defined here as the ultimate number of intracellular domain molecules reaching the nucleus, integrating ligand-mediated release and ...[more]

PMID: 26062937

Similar Datasets

Notch1 dose modulates endothelial gene expression

Project description:Purpose: To use RNA-Seq analysis of endothelial cell in various Notch1 alllels in order to determine transcrptional differencesas a consequence of Notch dose. Methods: Using a FACS sorting we generated high-throughput RNA-SEQ data of endothelials in various Notch1 alleles during development Results: Notch1 dose can alter gene expression in a subset of endothelial genes

2015-08-04 | GSE69276 | GEO

Mus musculus

Project description:Notch1 dose modulates endothelial gene expression

| PRJNA285070 | ENA

Discovery of biomarkers predictive of GSI response in triple negative breast cancer and adenoid cystic carcinoma

Project description:Next generation sequencing was used to identify Notch mutations in a large collection of diverse solid tumors. NOTCH1 and NOTCH2 rearrangements leading to constitutive receptor activation were confined to triple negative breast cancers (TNBC, 6 of 66 tumors). TNBC cell lines with NOTCH1 rearrangements associated with high levels of activated NOTCH1 (N1-ICD) were sensitive to the gamma-secretase inhibitor (GSI) MRK-003, both alone and in combination with pacitaxel, in vitro and in vivo, whereas cell lines with NOTCH2 rearrangements were resistant to GSI. Immunohistochemical staining of N1-ICD in TNBC xenografts correlated with responsiveness, and expression levels of the direct Notch target gene HES4 correlated with outcome in TNBC patients. Activating NOTCH1 point mutations were also identified in other solid tumors, including adenoid cystic carcinoma (ACC). Notably, ACC primary tumor xenografts with activating NOTCH1 mutations and high N1-ICD levels were sensitive to GSI, whereas N1-ICD low tumors without NOTCH1 mutations were resistant. Gene expression profiling for Notch-sensitive cancer cell lines using RNA-seq, each sample with triplicates

2014-08-14 | E-GEOD-59810 | biostudies-arrayexpress

O-Fucose glycans on mouse NOTCH1 from activated T cells of Fringe mutant mice

Project description:NOTCH1 (N1) is a transmembrane receptor that initiates a cell-cell signaling pathway controlling various cell fate specifications in metazoans. The addition of O-fucose by Protein O-fucosyltransferase 1 (POFUT1) to Epidermal Growth Factor-like (EGF) repeats in the N1 extracellular domain is essential for N1 function, and modification of O-fucose with GlcNAc by the Fringe family of glycosyltransferases modulates Notch activity. Prior cell-based studies showed that POFUT1 modifies EGF repeats containing the appropriate consensus sequence at high stoichiometry, while Fringe GlcNAc-transferases (LFNG, MFNG and RFNG) modify O-fucose on only a subset of NOTCH1 EGF repeats. Previous in vivo studies showed that each FNG affects naïve T cell development. To examine Fringe modifications of N1 expressed at a physiological level, we used mass spectral glycoproteomic methods to analyze O-fucose glycans of endogenous N1 from activated T cells obtained from mice lacking all Fringe enzymes, or expressing only a single FNG. While most O-fucose sites were modified at high stoichiometry, only EGF6, EGF16, EGF26, and EGF27 were extended in control T cells. Cell-based assays of N1 lacking fucose at each of those O-fucose sites revealed minor functional correlations in the EGF16 and EGF27 mutant with Notch ligand binding. In activated T cells expressing only LFNG, MFNG or RFNG alone, the extension of O-fucose with GlcNAc in the same EGF repeats was diminished, consistent with cooperative interactions when all three Fringes were present. The combined data open the door for the analysis of O-glycans on endogenous N1 derived from different cell types.

2022-08-12 | PXD031297 | Pride

Discovery of biomarkers predictive of GSI response in triple negative breast cancer and adenoid cystic carcinoma

2014-08-14 | GSE59810 | GEO

The downstream molecules of Notch signaling in vascular endothelial cell senescence

Project description:To further investigate the mechanism how the decline in Notch signaling induces premature senescence in endothelial cells, we performed microarray analysis and identified Id1 nd DUSP1 as the downstream molecules of Notch pathway. In quantitative PCR and western blot analyses, the expression level of Id1 and DUSP1 increased in Notch1 over-expressing endothelial cells and decreased in knockdown similar to the result of microarray. The gene expression of human unbilical endothelial vein cells (HUVEC) infected with retroviral vectors encoding Jagged1, Jagged1-shRNA, or Notch1-shRNA. HUVEC infected with empty vector was used as a control. In each genotypes, three independent lines at passage 8 were performed.

2012-08-28 | E-GEOD-40403 | biostudies-arrayexpress

Transcription profiling of human coronary artery endothelial cells treated with ADMA at 2uM (a pathophysiological dose) and 100uM (a pharmacological dose), for 24h

Project description:Asymmetric dimethylarginine (ADMA) is a naturally occurring inhibitor of nitric oxide synthesis that accumulates in wide range of diseases associated with endothelial dysfunction and enhanced atherosclerosis. Plasma ADMA has been implicated as a major novel cardiovascular risk factor, but the mechanisms by which low concentrations of ADMA produce adverse effects on the cardiovascular system are unclear. We have treated human coronary artery endothelial cells with ADMA at 2uM (a pathophysiological dose) and 100uM (a pharmacological dose), for 24h.

2005-09-01 | E-MEXP-377 | biostudies-arrayexpress

Activated Notch-induced transcriptional profile modulation in human primary dermal lymphatic endothelial cells

Project description:Human Notch1 intracellular domain (NICD) was overexpressed in human primary lymphatic endothelial cells (LECs) for 10 and 24 hours by adenovirus. A GFP-control adenovirus-infected cells (24hours) and uninfected cells were also analysed as controls. Total RNAs were harvested and subjected to Affymetrix U133A microarray. Human primary lymphatic endothelial cells (LECs) were isolated from human foreskin and cultured and expanded to population passages 5~6. Healthy subconfluent primary LECs were infected with adenovirus expressing human Notch1 intracellular domain (NICD) for 10 or 24 hours. In parallel, LECs were also infected with a GFP-expressing control adenovirus for 24 hours. Uninfected LECs were also used as a negative control in the same experiments

2010-03-20 | E-GEOD-20978 | biostudies-arrayexpress

Cancer-associated Notch receptor variants lead to O-fucosylation defects that can deregulate Notch signaling

Project description:NOTCH1 is a transmembrane receptor that initiates the Notch signaling pathway involved in embryonic development and maintenance of adult tissue homeostasis. The extracellular part of NOTCH1 is composed largely of EGF-like domains (EGFs) many of which can be O-fucosylated by protein O-fucosyltransferase 1 (POFUT1). O-fucosylation of NOTCH1 is necessary for its function. The Notch pathway is deregulated in many cancers, and alteration of POFUT1 has been reported in some cancers. Using the Biomuta and COSMIC databases, we selected 9 NOTCH1 variants that could cause a change in O-fucosylation of key EGFs. Cell-based N1 signaling assays, Notch ligand-binding assays and cell surface N1 analysis were used to determine the effect of each mutation on Notch activation. Then mass spectral glycoproteomic site mapping was used to identify alterations in the O-fucosylation of EGFs containing the selected mutation. One of the variants had few effects, two lead to a gain of function (GOF) and six to a loss of function (LOF). Most GOF and LOF could be associated with a change in O-fucosylation. Finally, by comparing our results with known NOTCH1 alterations in cancers from which our mutations originated, we were able to establish a correlation between our results and the known GOF or LOF of NOTCH1 in these cancers. This study shows that point mutations in NOTCH1 can lead to alterations in O-fucosylation that deregulate the Notch pathway and be associated with cancer processes.

2022-10-21 | PXD036345 | Pride

Deubiquitinase USP10 regulates Notch signaling in the endothelium

Project description:Notch signaling is critical for vascular morphogenesis by co-determining the sprouting behavior of endothelial cells. Here, we investigate the function of ubiquitin-specific peptidase 10 (USP10) in regulation of the turnover of the NOTCH1 intracellular domain. HUVEC were transfected with scrambled or USP10 targeting siRNA and then stimulated by treatment with DLL4 or control. RNA for analysis was isolated after 24 hours of DLL4 stimulation.

2019-04-26 | E-MTAB-7774 | biostudies-arrayexpress

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