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Dynamic gene expression in T-ALL following treatment and release of gamma-secretase inhibition [GRO-Seq]

ABSTRACT: Dynamic gene expression in T-ALL following treatment and release of gamma-secretase inhibition [GRO-Seq]

PROVIDER: PRJNA476373 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR7349480.fastq.gz	Fastqsanger.gz
	SRR7349490.fastq.gz	Fastqsanger.gz
	SRR7349500.fastq.gz	Fastqsanger.gz
	SRR7349510.fastq.gz	Fastqsanger.gz
	SRR7349481.fastq.gz	Fastqsanger.gz

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Dynamic gene expression in T-ALL following treatment and release of gamma-secretase inhibition [GRO-Seq]

Project description:Gro-seq analysis following NOTCH1 inhibition and release gave an ovierview of the kinetics of NOTCH1 dependent transcriptional regulatiion

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Project description:γ-Secretase is a transmembrane protease complex responsible for processing multiple type I transmembrane proteins, including the amyloid precursor protein (APP) and NOTCH. Using a proteomics-based screening approach, we found that dedicator of cytokinesis protein 2 (DOCK2) interacts with the γ-secretase complex component Nicastrin (NCSTN), regulating NCSTN N45-mannosylation and the effects of γ-secretase on NOTCH receptors. Both genetically depleting DOCK2 and pharmacologically targeting NCSTN mannosylation via Kifunensine ameliorate Notch-dependent leukemia progression in vivo. Together, these results reveal a mechanism by which γ-secretase specifically recognizes its substrate and provide a direction for treating Notch-related diseases.

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Neuronal γ-secretase regulates lipid metabolism, linking cholesterol to synaptic dysfunction in Alzheimer's disease

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Project description:This randomized phase I/II clinical trial is studying the side effects and best dose of gamma-secretase/notch signalling pathway inhibitor RO4929097 when given together with vismodegib and to see how well they work in treating patients with advanced or metastatic sarcoma. Vismodegib may slow the growth of tumor cells. Gamma-secretase/notch signalling pathway inhibitor RO4929097 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving vismodegib together with gamma-secretase/notch signalling pathway inhibitor RO4929097 may be an effective treatment for sarcoma.

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Identification of naturally short gamma-secretase substrates

Project description:The intramembrane protease gamma-secretase has broad physiological functions, but also contributes to Notch-dependent tumors and Alzheimer’s disease. To identify naturally short substrates and non-substrates of gamma-secretase, we used four human cell lines of different tissue origins, breast cancer MCF7 cells, cervix carcinoma HeLa cells, T cell leukemia Jurkat cells and lymphoma U937 macrophage-like cells. The cell lines were treated overnight with the established gamma-secretase inhibitor DAPT or DMSO as a control. The proteomes of membrane fractions were determined by nano-liquid chromatography-tandem mass spectrometry and label-free quantitative proteomics. TNFRSF12A, PTPRCAP and C16orf54 were identified as potential naturally short gamma-secretase substrates, whereas other proteins with a short ectodomain including ‘pituitary tumor-transforming gene 1-interacting protein’ (PTTG1IP) did not show an increased abundance upon DAPT treatment.

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CHO cells with enhanced and abolished gamma-secretase activity

Project description:γ-secretase is an intra-membrane-cleaving aspartyl protease implicated in the processing of a wide range of type I membrane proteins including the Notch receptor and the amyloid-β precursor protein (APP). It thus regulates a diverse array of cellular and biological processes including the differentiation of neuronal embryonic stem cells, or intestinal stem cells, with the latter controlling the self-renewing of the intestinal epithelium. Indeed, proteolysis of these proteins by γ-secretase triggers signaling cascades by releasing intracellular domains (ICDs) which, following association with adaptor proteins and nuclear translocation, modulate the transcription of different genes by binding directly to their promoters. The pronounced proliferative and regenerative effects of Notch signaling and its implication in the generation of the Aβ-peptides, makes γ-secretase a therapeutic target for several types of cancer and for Alzheimer’s disease. To investigate the broad effects of γ-secretase activity onto the cellular transcriptome, Chinese hamster ovary (CHO) cells with enhanced γ-secretase were compared to cells with abolished γ-secretase activity via a microarray designed for a genetically close species, mouse. Our findings will potentially help to decipher the biology of γ-secretase, including a better understanding of the roles of this enzyme in gene transcription.

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Project description:γ-Secretase is involved in the regulated intramembrane proteolysis (RIP) of a variety of integral membrane proteins and generates the amyloid peptide (Aβ) in Alzheimer’s Disease (AD). Microglia are centrally involved in AD, but the substrates and function of γ-secretase in these cells remain largely unstudied. Using a novel γ-Secretase Substrate Identification (G-SECSI) method, we identified 85 substrates, of which 59 were previously unknown, in stem cell derived microglia-like cells. More than 60% of those are signalling receptors possibly involved in cell state regulation. Inhibition of γ-secretase using Semagacestat or selective genetic knockout alters the expression of homeostatic (HM) and disease-associated (DAM) genes, in particular when microglia are exposed to amyloid plaques in vivo. Thus, γ-secretase regulates tonic signaling via a spectrum of substrates in microglia in steady state, and its blockage results in the defective transition to the DAM response in AD.

2023-11-14 | PXD039238 | Pride

Human CSF peptidomics of gamma secretase inhibition

Project description:Fifteen human healthy volunteers, divided into three groups, received a single dose of placebo or either 140 mg or 280 mg of the γ-secretase inhibitor semagacestat (LY450139). Endogenous peptides in CSF, sampled prior to administration of the drug and at six subsequent time points, were analyzed by liquid chromatography coupled to mass spectrometry, using isobaric labeling based on the tandem mass tag approach for relative quantification.

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Effect of a gamma secretase inhibitor on the T29 cell line

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Gene expression profiles of desmoid tumor cells treated with gamma-secretase inhibitor

Project description:Desmoid tumors (DTs) are rare mesenchymal monoclonal lesions that have a high risk of local recurrence but lack metastatic potential. Since the Notch pathway appears to be important in the carcinogenesis of several tumor types, in the past few years γ-secretase inhibitors (GSIs) have emerged as a potential therapeutic treatment by inhibiting cancer cell Notch signaling through NICD cleavage blockade. To investigate the antitumor effect of PF-03084014, a γ-secretase inhibitor, in DT models, cells treated with PF-03084014 were characterized by gene array analysis.

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