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Gene profiles induced by overexpression of wild-type and mutant Notch1 variants in MCF10A mammary epithelial cell line

ABSTRACT: Expression of a constitutively active Notch-1 intracellular domain (NICD) in MCF-10A cells was found to induce two distinct types of 3D structures: large, hyperproliferative structures and small, growth-arrested structures with reduced cell-to-matrix adhesion. These heterogeneous phenotypes reflect differences in Notch pathway activation levels. High Notch activity caused loss of cell adhesion and inhibition of proliferation, whereas low Notch activity maintained matrix adhesion and provoked a strong hyperproliferative response. In order to gain insight into the dosage-dependent transcriptional events triggered by Notch1 activation, gene expression profiles induced 48 hours after infection of MCF-10A cells with retroviral vectors expressing full-length Notch-1, L1601P+∆P, or NICD were compared. Full-length Notch-1 induced the weakest effect, L1601P+∆P induced an intermediate effect and NICD induced the strongest effect. Results provide insight into the dichotomous activites of Notch during development and tumorigenesis.

ORGANISM(S): Homo sapiens

PROVIDER: GSE20285 | GEO | 2010/03/12

SECONDARY ACCESSION(S): PRJNA125317

REPOSITORIES: GEO

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Gene profiles induced by overexpression of wild-type and mutant Notch1 variants in MCF10A mammary epithelial cell line

Project description:Expression of a constitutively active Notch-1 intracellular domain (NICD) in MCF-10A cells was found to induce two distinct types of 3D structures: large, hyperproliferative structures and small, growth-arrested structures with reduced cell-to-matrix adhesion. These heterogeneous phenotypes reflect differences in Notch pathway activation levels. High Notch activity caused loss of cell adhesion and inhibition of proliferation, whereas low Notch activity maintained matrix adhesion and provoked a strong hyperproliferative response. In order to gain insight into the dosage-dependent transcriptional events triggered by Notch1 activation, gene expression profiles induced 48 hours after infection of MCF-10A cells with retroviral vectors expressing full-length Notch-1, L1601P+âP, or NICD were compared. Full-length Notch-1 induced the weakest effect, L1601P+âP induced an intermediate effect and NICD induced the strongest effect. Results provide insight into the dichotomous activites of Notch during development and tumorigenesis. Twelve samples were harvested 48 h after retroviral infection with either vector control, full-length Notch1, Notch1 L1601P+âP, or NICD. Each condition was performed in triplicate.

2010-03-23 | E-GEOD-20285 | biostudies-arrayexpress

Gene expression signatures associated with PI3Kα-induced senescence

Project description:To investigate the mechanisms of PI3Kα-induced senescence, we performed a gene expression microarray analysis with MCF-10A/H and parental MCF-10A cells.

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Modeling Notch-induced tumor cell survival in the Drosophila ovary identifies cellular and transcriptional response to nuclear NICD accumulation

Project description:Notch is a conserved developmental signaling pathway that is dysregulated in many cancer types, most often through constitutive activation. Tumor cells with nuclear accumulation of the active Notch receptor, NICD, generally exhibit enhanced survival while patients experience poorer outcomes. To understand the impact of NICD accumulation during tumorigenesis, we developed a tumor model using the Drosophila ovarian follicular epithelium. Using this system we demonstrated that NICD accumulation contributed to larger tumor growth, reduced apoptosis, increased nuclear size, and fewer incidents of DNA damage without altering ploidy. Using bulk RNA sequencing we identified the key Notch-induced targets involved in cell survival and DNA damage repair which were alternatively regulated prior to tumor formation. Finally, using single-cell RNA sequencing we demonstrated that genes contributing to many pathways are altered following tumor formation in a cell-type-specific manner. Ectopically expressing NICD produced dysregulated expression of genes involved in cell death regulation, immune and stress response, JAK/STAT signaling, cytoskeletal binding, adhesion, polarity, and growth regulation. This valuable tumor model for nuclear NICD accumulation in adult Drosophila follicle cells has allowed us to better understand the specific role of nuclear NICD accumulation in tumor cells in tumor cell survival and tumor progression.

2021-09-19 | GSE182505 | GEO

RNA-seq analysis of MCF-10A human mammary epithelial cells following MYC activation

Project description:We profiled gene expression and splicing changes in MCF-10A human mammary epithelial cells expressing MYC fused to a portion of estrogen receptor (MYC-ER) (Eilers et al., 1989; Littlewood et al., 1995). We performed RNA-seq, in triplicate, on 3D-grown MCF-10A MYC-ER cells at 0, 8, and 24 hours (h) after 4-OHT-induced MYC activation. As a control for 4-OHT-induced effects, 3D-grown parental MCF-10A cells lacking the MYC-ER fusion protein were treated with 4-OHT at the same timepoints.

2022-07-11 | GSE181968 | GEO

Site-specific methylation of Notch1 controls the amplitude and duration of the Notch1 response

Project description:Physiologically, Notch signal transduction plays a pivotal role in differentiation; pathologically, Notch signaling contributes to the development of cancer. Transcriptional activation of Notch target genes involves cleavage of the Notch receptor in response to ligand binding, production of the Notch intracellular domain (NICD), and NICD migration into the nucleus and assembly of a coactivator complex. Posttranslational modifications of the NICD are important for its transcriptional activity and protein turnover. Deregulation of Notch signaling and stabilizing mutations of Notch1 have been linked to leukemia development. We found that the methyltransferase CARM1 (coactivator-associated arginine methyltransferase 1; also known as PRMT4) methylated NICD at five conserved arginine residues within the C-terminal transactivation domain. CARM1 physically and functionally interacted with the NICD-coactivator complex and was found at gene enhancers in a Notch-dependent manner. Although a methylation-defective NICD mutant was biochemically more stable, this mutant was biologically less active as measured with Notch assays in embryos of Xenopus laevis and Danio rerio. Mathematical modeling indicated that full but short and transient Notch signaling required methylation of NICD. Analysis of gene expression upon inactivation and activation of Notch signaling in Beko cells.

2015-03-26 | GSE62528 | GEO

CDK1 and CDK2 regulate NICD1 turnover and the periodicity of the segmentation clock

Project description:All vertebrates share a segmented body axis. Segments form from the rostral end of the presomitic mesoderm (PSM) with a periodicity that is regulated by the segmentation clock. The segmentation clock is a molecular oscillator that exhibits dynamic clock gene expression across the PSM with a periodicity that matches somite formation. Notch signalling is crucial to this process. Altering Notch intracellular domain (NICD) stability affects both the clock period and somite size. However, the mechanism by which NICD stability is regulated in this context is unclear. We identified a highly conserved site crucial for NICD recognition by the SCF E3 ligase, which targets NICD for degradation. We demonstrate both CDK1 and CDK2 can phosphorylate NICD in the domain where this crucial residue lies and that NICD levels vary in a cell cycle-dependent manner. Inhibiting CDK1 or CDK2 activity increases NICD levels both in vitro and in vivo, leading to a delay of clock gene oscillations and an increase in somite size.

2020-03-24 | PXD013038 | Pride

Site-specific methylation of Notch1 controls the amplitude and duration of the Notch1 response

2015-03-26 | E-GEOD-62528 | biostudies-arrayexpress

Gene expression analysis in mouse mature T-cells either upon overexpression of the NICD or knockout of H2A.Z

Project description:Genes induced by the Notch-Intracellular domain (NICD) in mouse mature T-cells (MT) are identifed. Among the induced Notch target genes we also identify those genes, which are regulated by the histone variant H2A.Z

2018-06-21 | GSE111029 | GEO

Proliferation-independent regulation of organ size by Notch signaling

Project description:Purpose: To identify genes that are transcriptionally controlled by Notch signaling during zebrafish lateral line proneuromast formation. Methods: We isolated primordium cells from dissected tails of 36 hpf Tg((cldnB:GFP);Tg(cldnB:gal4) x Tg(UAS:nicd)) and sibling Tg((cldnB:GFP);Tg(cldnB:gal4)) embryos by FACS and performed RNASeq analysis. Results: Using an optimized data analysis workflow, we mapped about 26 million sequence reads per sample to the zebrafish genome (build danRer10) and identified 32,105 transcripts in the dissociated tails of WT and NICD zebrafish with TopHat workflow. Approximately 2% of the transcripts showed differential expression between the WT and NICD tails, with a fold change ≥0.5 and p value <0.01. Conclusion: RNASeq analyses revealed that Notch signaling cell-autonomously induces apical constriction and cell adhesion.

2017-01-05 | GSE86571 | GEO

Identification of genes are regulated by AURKA at transcription level

Project description:Purpose: AURKA plays an important role in breast cancer development. Exploring the gene expression profiles regulated by AURKA will facilitate to understand the mechanism which is responsible for AURKA induced breast cancer development. Results: We found that 350 genes were significantly up-regulated during AURKA overexpression in MCF-10A cells, 346 genes were significantly down-regulated during AURKA overexpression in MCF-10A cells. Conclusions: Our study indicated that 696 differentially expressed genes might contribute to AURKA induced breast cancer development. MCF-10A cells overexpressed AURKA or the empty vector were subjected to RNA extraction. The resulted RNA samples were performed RNA-sequencing analyses of gene expression profiles.

2015-10-28 | E-GEOD-57931 | biostudies-arrayexpress

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