Notch1 glycopeptide in Eogt mutant
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus Musculus (mouse)
SUBMITTER: Tetsuya Okajima
PROVIDER: PXD018555 | JPOST Repository | Tue May 05 00:00:00 BST 2020
REPOSITORIES: jPOST
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Project description:To unravel molecular targets involved in glycopeptide resistance, three isogenic strains of Staphylococcus aureus with different susceptibility levels to vancomycin or teicoplanin were subjected to whole-genome microarray-based transcription and quantitative proteomic profiling. Quantitative proteomics performed on membrane extracts showed exquisite inter-experimental reproducibility permitting the identification and relative quantification of >30% of the predicted S. aureus proteome. In the absence of antibiotic selection pressure, comparison of stable resistant and susceptible strains revealed 94 differentially expressed genes and 178 proteins. As expected, only partial correlation was obtained between transcriptomic and proteomic results during stationary-phase. Application of massively parallel methods identified one third of the complete proteome, a majority of which was only predicted based on genome sequencing, but never identified to date. Several over‑expressed genes represent previously reported targets, while series of genes and proteins possibly involved in the glycopeptide resistance mechanism were discovered here, including regulators, global regulator attenuator, hyper‑mutability factor or hypothetical proteins. Gene expression of these markers was confirmed in a collection of genetically unrelated strains showing altered susceptibility to glycopeptides. Our proteome and transcriptome analyses have been performed during stationary‑phase of growth on isogenic strains showing susceptibility or intermediate level of resistance against glycopeptides. Altered susceptibility had emerged spontaneously after infection with a sensitive parental strain, thus not selected in vitro. This combined analysis allows the identification of hundreds of proteins considered, so far as hypothetical protein. In addition, this study provides not only a global picture of transcription and expression adaptations during a complex antibiotic resistance mechanism but also unravels potential drug targets or markers that are constitutively expressed by resistant strains regardless of their genetic background, amenable to be used as diagnostic targets. Keywords: Molecular markers, antibiotic resistance, glycopeptides, growth-phase
2007-03-09 | GSE5188 | GEO
Project description:Mutations in the Notch1 receptor and delta-like 3 (Dll3) ligand cause global disruptions in axial segmental patterning. Genetic interactions between members of the notch pathway have previously been shown to cause patterning defects not observed in single gene disruptions. We examined Dll3-Notch1 compound mouse mutants to screen for potential gene interactions. While mice heterozygous at either locus appeared normal, 30% of Dll3-Notch1 double heterozygous animals exhibited localized, stochastic segmental anomalies similar to human congenital vertebral defects. Unexpectedly, double heterozygous mice also displayed statistically significant decreases in mandibular height and elongated maxillary hard palate. Examination of somite-stage embryos and perinatal anatomy and histology did not reveal any organ defects, so we used microarray-based analysis of Dll3 and Notch1 mutant embryos to identify gene targets that may be involved in notch-regulated segmental or craniofacial development. Therefore, Dll3-Notch1 double heterozygous mice model human congenital scoliosis and craniofacial disorders. Experiment Overall Design: Given the reduced penetrance and stochastic nature of the segmental and craniofacial defects in Dll3-Notch1 double heterozygous animals, we next sought to identify candidate genes that may be down or up-regulated in Dll3 and Notch1 homozygous mutant embryos during development of these structures. We carried out microarray analysis using Affymetrix MOE430 microarrays, comparing 9.5 dpc homozygous embryos in duplicate to littermates with wild-type alleles at both loci, and comparing with heterozygous littermate embryos. Affymetrix analysis software (Microarray Suite 5.0) was used to determine whether gene probes were present, marginal or absent. Probes with present flags in replicates of Dll3, Notch1, or embryos with wild-type alleles at both loci were considered present for further analysis. Altogether, out of 22,690 probe sets on the MOE430A array, we identified 12,820 probes that were present in replicates of at least one genotypic group. To identify genes that were increased or decreased in expression in mutant embryos, we carried out robust multichip average (RMA) normalization of microarray data sets using the RMA module of Genespring GX 7.3 (Agilent). After RMA normalization, housekeeping genes such as Gapdh showed steady expression (probe AFFX-GapdhMur/M32599_M_at, normalized expression 1.00 ± 0.02). As a general indicator of variability between samples, we calculated Pearsonâs correlation coefficients. We found that the correlations between duplicates were moderately high: wild-type embryos (0.623), Dll3 embryos (0.584), Notch1 embryos (0.531).
2008-06-15 | E-GEOD-8027 | biostudies-arrayexpress
Project description:Mutations of SF3B1 in CLL induce alternative splicing in multiple transcripts, including DVL2. DVL2 in turn can act as a negative regulator of NOTCH1 signaling. Gene Expression Profile (GEP) was used to investigate the activation of the NOTCH1 pathway in presence of alternatively spliced DVL2.
2019-09-07 | GSE137024 | GEO
Project description:Stabilizing mutations of NOTCH1 have been identified in about 10% of chronic lymphocytic leukemia (CLL) cases at diagnosis, with a higher frequency in unmutated IGHV (IGHV-UM) CLL, chemorefractory CLL and CLL in advanced disease phases. Clinically, the presence of NOTCH1 mutations is an independent predictor of overall survival in CLL and associates with resistance to anti-Cd20 immunotherapy. The Gene Expression Profile was generated to identify the peculiar molecular signatures of NOTCH1 mutated CLL in the context of IGHV-UM CLL.
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Project description:Senescence, a persistent form of cell cycle arrest, is often associated with a diverse secretome, which provides complex downstream functionality for senescent cells within the tissue microenvironment. We show that oncogene-induced senescence (OIS) is accompanied by a dynamic fluctuation of NOTCH1 activity, which drives a TGF-β-rich secretome, whilst suppressing the senescence-associated pro-inflammatory secretome through inhibition of C/EBPβ. NOTCH1 and NOTCH1-driven TGF-β contribute to ‘lateral induction of senescence’ through a juxtacrine NOTCH-JAG1 pathway. In addition, NOTCH1 inhibition during senescence facilitates upregulation of pro-inflammatory cytokines, promoting lymphocyte recruitment and senescence surveillance in vivo. Because enforced activation of NOTCH1 signalling confers a near mutually exclusive secretory profile compared to typical senescence, our data collectively indicate that the dynamic alteration of NOTCH1 activity during senescence dictates a functional balance between these two distinct secretomes: one representing TGF-β and the other pro-inflammatory cytokines, highlighting that NOTCH1 is a temporospatial controller of secretome composition.
2016-08-03 | PXD004168 | Pride
Project description:Stabilizing mutations of NOTCH1 have been identified in about 10% of chronic lymphocytic leukemia (CLL) cases at diagnosis, with a higher frequency in unmutated IGHV (IGHV-UM) CLL, chemorefractory CLL and CLL in advanced disease phases. Clinically, the presence of NOTCH1 mutations is an independent predictor of overall survival in CLL and associates with resistance to anti-Cd20 immunotherapy. The Gene Expression Profile was generated to identify the peculiar molecular signatures of NOTCH1 mutated CLL in the context of IGHV-UM CLL. Constitutive gene expression in CLL cells bearing or not NOTCH1 mutation (c.7541_7542delCT). Five samples were selected for each category (WT vs MUT).
2016-03-01 | E-GEOD-75122 | biostudies-arrayexpress
Project description:To formally address the tumor suppressor activity of Sh2b3 in vivo, we tested the interaction between oncogenic NOTCH1 and Sh2b3 loss in a retroviral- transduction bone marrow transplantation model of NOTCH-induced T-ALL Forced expression of activated NOTCH1 in this model typically results in full leukemia transformation 5-10 weeks later. We performed microarray gene expression analysis of Sh2b3 wild type and Sh2b3–/– NOTCH1 induced leukemias
2013-11-06 | E-GEOD-44025 | biostudies-arrayexpress
Project description:To formally address the biological activity of Hes1 in vivo, we tested the interaction between oncogenic NOTCH1 and acute Hes1 loss in a retroviral-transduction bone marrow transplantation model of NOTCH-induced T-ALL Forced expression of activated NOTCH1 in this model typically results in full leukemia transformation 5-10 weeks later. We performed microarray gene expression analysis of Hes1 wild type and Hes1-/- NOTCH1 induced leukemias
2015-05-07 | E-GEOD-65863 | biostudies-arrayexpress
Project description:Deep learning has achieved a notable success in mass spectrometry-based proteomics and is now emerging in glycoproteomics. While various deep learning models can predict fragment mass spectra of peptides with good accuracy, they cannot cope with the non-linear glycan structure in an intact glycopeptide. Herein, we propose a deep learning-based approach for the prediction of fragment spectra of intact glycopeptides. Our model adopts tree-structured long-short term memory networks to process the glycan moiety and a graph neural network architecture to incorporate potential fragmentation pathways of a specific glycan structure. This feature is beneficial to model explainability and differentiation ability of glycan structural isomers. We further demonstrated that predicted spectral libraries can be used for analyzing DIA data of glycopeptides as a supplement for library completeness. We expect that this work will provide a valuable deep learning resource for glycoproteomics.
2023-12-17 | PXD045248 | iProX
Project description:The O-GlcNAc modification of Notch receptors regulates Notch ligand interactions in a manner distinct from other forms of O-glycans on epidermal growth factor-like (EGF) repeats of Notch receptors. Although many proteins, besides Notch receptors, are expected to be O-GlcNAcylated by EGF domain-specific O-GlcNAc transferase (EOGT), only a small number of proteins have been reported to be modified in vivo, and elongated O-GlcNAc glycans have not been extensively explored. To extend our view of the specificity and variety of the glycan modification, we conducted a comprehensive analysis of O-GlcNAc glycans on NOTCH1 in mammals. Mass spectrometric analysis of NOTCH1 fragments expressed in HEK293T cells revealed that several EGF domains with putative O-GlcNAcylation sites were hardly modified with O-GlcNAc. Although amino acid residues before the modification site are preferentially occupied with aromatic residues, Phe and Tyr are preferrable to Trp for the apparent modification with O-GlcNAc. Furthermore, a minor form of fucosylated O-GlcNAc glycans was detected in a subset of EGF domains. Fucosylation of O-GlcNAc glycans was enhanced by FUT1, FUT2, or FUT9 expression. The FUT9-dependent Lewis X epitope was confirmed by immunoblotting using an anti-Lewis X antibody. As expected from the similarity in the glycan structures, the Lexis X antigen was detected on O-fucose glycans. Notably, the Lewis X structure on O-glycans was identified in endogenous NOTCH1 isolated from MCF7 cells. Our results refined the putative consensus sequence for the EOGT-dependent extracellular O-GlcNAc modification in mammals and revealed the structural diversity of functional Notch O-glycans.
2022-11-03 | PXD029528 | JPOST Repository