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Expression profiling after ICAP1 or constitutive active NOTCH1 over expression in human umbilical vein endothelial cells

ABSTRACT: ICAP1 (also known as ITG1BP1) is a protein interaction partner of beta1-integrins and the cerebral cavernous malformation protein 1 (CCM1, also known as KRIT1). In mice Icap1 plays an important role for bone development. The function of ICAP1 in endothelial cells is poorly understood. However, the interactions with beta1-integrins and CCM1 suggest that ICAP1 should play an important role also in endothelial cells. We obtained data that ICAP1 might activate the Delta-Notch signaling cascade, a critical regulator of endothelial proliferation, migration and sprouting angiogenesis. This genome-wide expression analysis is aimed to unravelling novel mechanisms or signaling pathways how ICAP1 functions in endothelial cells. Secondly, this study aimed at defining novel target genes of Notch signaling and finally to compare the gene expression patterns of ICAP1 and NOTCH1. We used human umbilical vein endothelial cells (HUVEC) as a model system to study ICAP1 and NOTCH1 functions after adenoviral over expression in comparison to GFP over expression as control. The results of this experiment suggest that ICAP1 and NOTCH1 control a series of genes involved in cell proliferation, migration and angiogenesis. A high proportion of ICAP1-regulated genes is also regulated by NOTCH1 in a very similar manner.

ORGANISM(S): Homo sapiens

PROVIDER: GSE18035 | GEO | 2010/07/02

SECONDARY ACCESSION(S): PRJNA119889

REPOSITORIES: GEO

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Expression profiling after ICAP1 or constitutive active NOTCH1 over expression in human umbilical vein endothelial cells

Project description:ICAP1 (also known as ITG1BP1) is a protein interaction partner of beta1-integrins and the cerebral cavernous malformation protein 1 (CCM1, also known as KRIT1). In mice Icap1 plays an important role for bone development. The function of ICAP1 in endothelial cells is poorly understood. However, the interactions with beta1-integrins and CCM1 suggest that ICAP1 should play an important role also in endothelial cells. We obtained data that ICAP1 might activate the Delta-Notch signaling cascade, a critical regulator of endothelial proliferation, migration and sprouting angiogenesis. This genome-wide expression analysis is aimed to unravelling novel mechanisms or signaling pathways how ICAP1 functions in endothelial cells. Secondly, this study aimed at defining novel target genes of Notch signaling and finally to compare the gene expression patterns of ICAP1 and NOTCH1. We used human umbilical vein endothelial cells (HUVEC) as a model system to study ICAP1 and NOTCH1 functions after adenoviral over expression in comparison to GFP over expression as control. The results of this experiment suggest that ICAP1 and NOTCH1 control a series of genes involved in cell proliferation, migration and angiogenesis. A high proportion of ICAP1-regulated genes is also regulated by NOTCH1 in a very similar manner. Human umbilical vein endothelial cells were transduced with adenovirus expressing ICAP1, NOTCH1 (only the constitutive active intracellular domain) or GFP as control. 36 hours after transduction total RNA was isolated from duplicates for genome-wide expression analysis biological replicate: GFP_1, GFP_2 biological replicate: NOTCH1_1, NOTCH1_2 biological replicate: ICAP1_1, ICAP1_2

2010-07-30 | E-GEOD-18035 | biostudies-arrayexpress

Gene expression profile after CCM1 over expression in human umbilical vein endothelial cells

Project description:CCM1 (also known as KRIT1) is critical regulator of endothelial cell biology. Mutations in CCM1 can lead to the formation of cerebral cavernous malformations (CCM). CCM lesions are frequent in the human population; however, their pathogenesis is poorly understood. This genome-wide expression analysis is aimed to unravelling novel mechanisms how CCM1 executes its functions in endothelial cells. We used human umbilical vein endothelial cells (HUVEC) as a model system to study CCM1 functions after adenoviral over expression. The results of this experiment suggest that CCM1 is a critical regulator of endothelial cell cycle control and proliferation as well as migration and angiogenesis. This fits well to the roles of CCM1 in HUVEC which indeed acts as a negative regulator of angiogenesis. Human umbilical vein endothelial cells were transduced with adenovirus expressing CCM1 or GFP as control. 48 hours after transduction total RNA was isolated from duplicates for genome-wide expression analysis biological replicate: GFP rep1, GFP rep2 biological replicate: CCM1 rep1, CCM1 rep2

2010-06-16 | E-GEOD-18014 | biostudies-arrayexpress

Gene expression profile after CCM1 over expression in human umbilical vein endothelial cells

2010-06-08 | GSE18014 | GEO

Notch and VEGF pathways play distinct but complementary roles in tumor angiogenesis

Project description:We asked whether combining Notch and VEGF blockade would enhance suppression of tumor angiogenesis and growth, using the NGP neuroblastoma model. NGP tumors were engineered to express a Notch1 decoy construct (N1D), which restricts Notch signaling, and then treated with either the anti-VEGF antibody bevacizumab or vehicle. Combining Notch and VEGF blockade led to blood vessel regression, increasing endothelial cell apoptosis and disrupting pericyte coverage of endothelial cells. Combined Notch and VEGF blockade did not affect tumor weight, but did additively reduce tumor viability. Our results indicate that Notch and VEGF pathways play distinct but complementary roles in tumor angiogenesis, and show that concurrent blockade disrupts primary tumor vasculature and viability further than inhibition of either pathway alone. 6 neuroblastoma tumors were transfected with Notch1 decoy, 6 with Notch1 decoy and treated with bevacizumab, 6 tumors treated with bevacizumab, and 6 control tumors were profiled by human 133A 2.0 arrays

2013-12-01 | E-GEOD-48880 | biostudies-arrayexpress

miR-221 is required for endothelial tip cell behaviors during vascular development

Project description:Through deep sequencing and functional screening in zebrafish, we find that miR-221 is essential for angiogenesis. miR-221 knockdown phenocopied defects associated with loss of the tip cell-expressed Flt4 receptor. Furthermore, miR-221 was required for tip cell proliferation and migration, as well as tip cell potential in mosaic blood vessels. miR-221 knockdown also prevented “hyper-angiogenesis” defects associated with Notch deficiency and miR-221 expression was inhibited by Notch signaling. Finally, miR-221 promoted tip cell behavior through repression of two targets: cyclin-dependent kinase inhibitor 1b (cdkn1b) and phosphoinositide-3-kinase regulatory subunit 1 (pik3r1). These results identify miR-221 as an important regulatory node through which tip cell migration and proliferation are controlled during angiogenesis. Identification of endothelial-expressed microRNA from FACS-isolated zebrafish endothelial cells.

2012-02-28 | E-GEOD-35078 | biostudies-arrayexpress

HEK NICD AP-MS - Notch signaling is a core patterning module for vascular morphogenesis, which co-determines the sprouting behaviour of endothelial cells (ECs)

Project description:Notch signaling is a core patterning module for vascular morphogenesis, which co-determines the sprouting behaviour of endothelial cells (ECs). Tight quantitative and temporal control of Notch activity is essential for vascular development, yet the details of Notch regulation in ECs are incompletely understood. We found that ubiquitin-specific peptidase 10 (USP10) interacted with the NOTCH1 intracellular domain (NICD1) to slow the ubiquitin-dependent turnover of this short-lived form of the activated NOTCH1 receptor. Accordingly, inactivation of USP10 reduced NICD1 abundance and stability, and diminished Notch-induced target gene expression in ECs. In mice, loss of endothelial Usp10 increased vessel sprouting and partially restored the patterning defects caused by ectopic expression of NICD1. Thus, USP10 functions as an NICD1 deubiquitinase, which fine-tunes endothelial Notch responses during angiogenic sprouting.

2019-04-11 | PXD013192 | Pride

Notch and VEGF pathways play distinct but complementary roles in tumor angiogenesis

2013-12-01 | GSE48880 | GEO

Notch signaling rapidly regulates the expression of the small GTPase RND1 and a diverse endothelial transcriptome

Project description:Endothelial Notch signaling regulates transcription of many downstream effectors controlling sprouting, migration, proliferation, barrier formation, and other phenotypes. However, endothelial-relevant Notch targets are largely uncharacterized. Few are studied in depth, and many transient, early response Notch targets are yet to be described. We therefore determined the Notch early response transcriptional profile in several experimentally relevant in vivo and in vitro contexts: ligand-specific or EGTA-induced Notch activation in different primary endothelial cells, and gamma secretase-mediated Notch inhibition in neonatal brain endothelium in a RiboTag mouse model. The intersection of these profiles reveals a core set of early Notch-responsive targets. Among these are effectors in GPCR signaling, not previously implicated downstream of Notch signaling. We demonstrate the Rho GTPase RND1 is a direct Notch transcriptional target and required for Notch control of sprouting angiogenesis, endothelial migration and Ras activity.

2022-01-11 | GSE163568 | GEO

Inhibition of endothelial Notch signaling attenuates inflammation [ChIP-Seq]

Project description:Vascular endothelial cells upregulate the Notch ligand Jagged1 in response to inflammatory activation. Here we show that abrogation of endothelial Notch1 signaling impairs induction of key inflammatory target genes. Accordingly, inducible endothelial-targeted knockout of the canonical Notch transcription factor RBPJ reduces inflammation in a murine model of contact hypersensitivity, while overexpression of constitutive active Notch1 has the opposite effect. We show that the proinflammatory role of Notch1 can be attributed to direct genomic priming of the inflammatory landscape involving crosstalk with NF-κB/RelA and selective activation of enhancers associated with Notch-dependent inflammatory genes. This is the first evidence that canonical Notch signaling supports endothelial activation in response to inflammatory cytokines on the chromatin level.

2018-08-29 | GSE87552 | GEO

Depletion of beta1 integrins in triple negative breast cancer cells causes extensive alterations in gene expression profiles

Project description:Interactions with the extracellular matrix (ECM) through integrin adhesion receptors provide cancer cells with physical and chemical cues that act in concert with growth factors to support survival and proliferation. Preclinical studies testing beta1 integrin antagonists in (breast) cancer models have shown inhibition of tumor growth and sensitization to radio- or chemotherapy and these strategies are currently evaluated in clinical trials. Here, we show that disruption of beta1 integrin-mediated ECM adhesion attenuates breast tumor growth but dissemination to the lungs from such small tumors can be markedly enhanced. beta1 integrin downregulation induces compensatory upregulation of beta3 integrins, but increased beta3 expression does not lead to enhanced lung metastasis. Instead, beta1 integrin downregulation in human and mouse triple negative, E-cadherin positive breast cancer cells elicits a switch from collective invasion to individual cell migration in 3D ECM. This involves alterations in the TGFbeta-BMP signaling network shifting the balance between miR-200 and ZEB, which causes a block in E-cadherin transcription. The switch is fully reversible: restored beta1 expression reinstates E-cadherin expression and cell cohesion. Moreover, restoring the network at the level of TGFbetaR, ZEB/miR-200 balance, or E-cadherin, restores cohesion and prevents the induction of lung metastasis without affecting tumor growth. These findings reveal that integrin-mediated ECM-attachments regulate a signaling network in control of epithelial characteristics that suppress metastatic spread. This raises concerns with respect to the use of beta1 integrins as cancer drug targets

2014-02-11 | E-MTAB-2185 | biostudies-arrayexpress

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