Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Effect of treating HRMVECs with nutlin-3 and/or norrin

ABSTRACT: To identify transcripts controlled by elevated P53 in HRMVECs we inhibited the MDM2/P53 interaction using nutlin-3. To identify cross-talk of P53 and beta-catenin dependent signaling, the experiment was performed in the presence or absence of the frizzled4 ligand norrin. Expression of beta-catenin-dependent signaling response genes induced by norrin, e.g., AXIN2 and APCDD1, were inhibited by nutlin-3. Nutlin-3 furthermore altered the expression of several gene sets, e.g., known p53 regulated genes (e.g., CDKN1A, MDM2), genes that potentially regulate beta-catenin-dependent signaling (including NCAPH, NEURL2, DRAXIN, DKK1), mediators of blood-retina barrier function (including SOX18, KIF11, ABCG2, MFSD2A), and mediators of inflammatory signaling and leukocyte extravasation (including ICAM1, CCL2, SELE, and CXCL1). The gene expression changes mediating inflammatory signaling and leuokocyte interactions substantially overlap with those expression changes observed in endothelial cells under high glucose conditions and diabetes mellitus.

ORGANISM(S): Homo sapiens

PROVIDER: GSE242783 | GEO | 2025/06/30

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

The transcriptional response to Norrin/Fz4 signaling

Project description:Using mice with targeted gene mutations, we identify (1) distinct roles for different canonical Wnt signaling components in central nervous system (CNS) vascular development and in the specification of the blood-brain and blood-retina barriers (BBB and BRB) and (2) differential sensitivities of the vasculature in various CNS regions to perturbations in canonical Wnt signaling components. We find nearly equivalent roles for Lrp5 and Lrp6 in brain vascular development and barrier maintenance but a dominant role for Lrp5 in the retinal vasculature, an especially high sensitivity of the BBB in the cerebellum and pons/interpeduncular nuclei to decrements in canonical Wnt signaling, and plasticity in the barrier properties of mature CNS vasculature. Brain and retinal vascular defects caused by loss of Norrin/Frizzled4 signaling can be fully rescued by stabilizing beta-catenin, and loss of beta-catenin’s transcriptional activation domain or expression of a dominant negative Tcf4 recapitulates the vascular development and barrier defects seen with loss of receptor, co-receptor, or ligand, indicating that Norrin/Frizzled4 signaling acts predominantly by beta-catenin-dependent transcriptional regulation. This work strongly supports a model in which identical or nearly identical canonical Wnt signaling mechanisms mediate neural tube and retinal vascularization and maintain the BBB and BRB. Total retina RNA from P10 WT, NdpKO, Ctnnb1flex3/+;Pdgfb-CreER, and NdpKO;Ctnnb1flex3/+;Pdgfb-CreER mice was subjected to RNAseq

2014-06-05 | E-GEOD-56461 | biostudies-arrayexpress

Transcription profiling of mouse cultured retinal endothelial cells - regulation by Norrin-Frizzled4 signaling (Super Series)

Project description:This SuperSeries is composed of the following subset Series:; GSE16691: Transcriptional regulation by Norrin-Frizzled4 signaling in the embryonic yolk sac; GSE16703: Long-term effect on the transcriptome of a decrement in Norrin/Frizzled4/Lrp signaling in retinal endothelial cells; GSE16705: Transcriptional response to Frizzled4 signaling in cultured retinal endothelial cells; GSE16707: Long-term effect on the transcriptome of loss of Frizzled4 signaling in cerebellar endothelial cells Experiment Overall Design: Refer to individual Series

2009-10-10 | E-GEOD-16841 | biostudies-arrayexpress

The transcriptional response to Norrin/Fz4 signaling

2014-06-05 | GSE56461 | GEO

Norrin-dependent gene expression in Patched mouse medulloblastoma

Project description:Medulloblastoma (MB), a tumor of the cerebellum, is the most common malignant brain tumor in children. One third of all human MB exhibits a gene expression signature of Sonic hedgehog (Shh) signaling. Hedgehog (Hh) pathway inhibitors have shown efficacy in clinical trials for MB, however, tumors develop resistance to these compounds, highlighting the need to identify additional therapeutic targets for treatment. We have identified a role for Norrin signaling in tumor initiation in the Patched (Ptch) mouse model of MB. Norrin is a secreted factor that functions as an atypical Wnt by binding to the Frizzled4 (Fzd4) receptor on endothelial cells to activate canonical beta-catenin-mediated Wnt signaling pathway. In the cerebellum, activation of Norrin/Fzd4 signaling is required for the establishment and maintenance of the blood brain barrier (BBB). We have identified a role for Norrin signaling in the stroma as a potent tumor inhibitory signal. Inactivation of Norrin in Ptch+/- mice significantly shortens latency and increases MB incidence. This phenotype is associated with an increased frequency of pre-tumor lesions and their conversion to malignancy. In this context, loss of Norrin signalling in endothelial cells is associated with an accelerated transition to a pro-tumor stroma characterized by vascular permeability, inflammation and angiogenic remodelling. Accordingly, loss of Ndp significantly alters the stromal gene expression signature of established Ptch MB.

2016-10-12 | GSE81963 | GEO

Norrin-dependent gene expression in cerebellar granule neuron progenitors

2016-10-12 | GSE81962 | GEO

Project description:Transcriptional regulation by Norrin-Frizzled4 signaling

| PRJNA117609 | ENA

Interruption of p53-MDM2 Interaction by Nutlin-3a in Human Lymphoma Cell Models Initiates a Cell-Dependent Global Effect on Transcriptome and Proteome Level

Project description:In most lymphomas, p53 signaling pathway is inactivated by various mechanisms independent to p53 gene mutations or deletions. In many cases, p53 function is largely regulated by alterations in the protein abundance levels by the action of E3 ubiquitin-protein ligase MDM2, targeting p53 to proteasome-mediated degradation. In the present study, an integrating transcriptomics and pro-teomics analysis was employed to investigate the effect of p53 activation by a small-molecule MDM2-antagonist, nutlin 3a, on three lymphoma cell models following p53 activation. Our analy-sis revealed a system-wide nutlin 3a-associated effect in all examined lymphoma types, identifying in total of 4037 differentially affected proteins involved in a plethora of pathways, with significant heterogeneity among lymphomas. Our findings include known p53-targets and novel p53 activa-tion effects, involving transcription, translation, or degradation of protein components of path-ways, such as a decrease in key members of PI3K/mTOR pathway, heat-shock response, and gly-colysis, and an increase in key members of oxidative phoshosphorylation, autophagy and mito-chondrial translation. Combined inhibition of HSP90 or PI3K/mTOR pathway with nutlin 3a-mediated p53-activation enhanced the apoptotic effects suggesting a promising strategy against human lymphomas. Integrated omic profiling after p53 activation offered novel insights on the regulatory role specific proteins and pathways may have in lymphomagenesis.

2023-07-30 | PXD009290 | Pride

Cooperation of Nutlin-3a and a Wip1 inhibitor to induce p53 activity

Project description:Targeting the Mdm2 oncoprotein by drugs has the potential of re-establishing p53 function and tumor suppression. However, Mdm2-antagonizing drug candidates, e. g. Nutlin-3a, often fail to abolish cancer cell growth sustainably. To overcome these limitations, we inhibited Mdm2 and simultaneously a second negative regulator of p53, the phosphatase Wip1/PPM1D. When combining Nutlin-3a with the Wip1 inhibitor GSK2830371 in the treatment of p53-proficient but not p53-deficient cells, we observed enhanced phosphorylation (Ser 15) and acetylation (Lys 382) of p53, increased expression of p53 target gene products, and synergistic inhibition of cell proliferation. Surprisingly, when testing the two compounds individually, largely distinct sets of genes were induced, as revealed by deep sequencing analysis of RNA. In contrast, the combination of both drugs led to an expression signature that largely comprised that of Nutlin-3a alone. Moreover, the combination of drugs, or the combination of Nutlin-3a with Wip1-depletion by siRNA, activated p53-responsive genes to a greater extent than either of the compounds alone. Simultaneous inhibition of Mdm2 and Wip1 enhanced cell senescence and G2/M accumulation. Taken together, the inhibition of Wip1 might fortify p53-mediated tumor suppression by Mdm2 antagonists.

2016-05-02 | GSE80716 | GEO

Genome-wide map of p53 binding sites by ChIP-seq in human lymphoblastoid cell lines treated with nutlin-3

Project description:We have used chromatin immune-precipitation with parallel sequencing (ChIP-Seq) technology to identify genome-wide p53 binding in human lymphoblastoid cell lines treated with a MDM2 inhibitor nutlin-3 ChIP-Seq analysis of p53 binding sites in human lymphoblastoid cells treated with nutlin-3 or vehicle

2013-10-23 | E-GEOD-46992 | biostudies-arrayexpress

transcriptional response to endothelial cell-specific inactivation of Tspan12 in the mature retina

Project description:Blood-retina barrier (BRB) formation and retinal angiogenesis depend on beta-catenin signaling induced by the ligand norrin (NDP), the receptor frizzled4 (FZD4), co-receptor LRP5, and the tetraspanin TSPAN12. Impaired NDP/FZD4 signaling causes familial exudative vitreoretinopathy (FEVR), which may lead to blindness. Endothelial-cell specific inactivation of the Tspan12 gene at P28 using a Cdh5-CreERT2 driver shows that TSPAN12 functions in ECs to promote vascular morphogenesis and BRB formation in developing mice, and BRB maintenance in adult mice. 12 month after Tspan12 inactivation and loss of BRB maintenance with massive IgG and albumin extravasation we observe complement activation, cystoid edema, and impaired beta-wave in electroretinograms. RNA-Seq 6 month after Tspan12 inactivation provides a detailed view on the transcriptional response, including activation of antibody effector systems (complement and Fc receptors), inflammation and microglia responses, extracellular matrix organization and remodeling, and other responses.

2018-10-29 | GSE113878 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data