Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

The human ion channel TRPM2 modulates cell survival in neuroblastoma through E2F1 and FOXM1

ABSTRACT: Transient receptor potential channel melastatin 2 (TRPM2) is highly expressed in cancer and has an essential function in preserving viability through maintenance of mitochondrial function and antioxidant response. Here, the role of TRPM2 in cell survival was examined in neuroblastoma cells deleted of TRPM2 with CRISPR technology. Viability was significantly decreased in TRPM2 knockout after doxorubicin treatment. RNA sequence analysis and RT-qPCR revealed reduced RNAs encoding master transcription regulators FOXM1 and E2F1/2 and downstream cell cycle targets including Cyclin B1, CDK1, PLK1, and CKS1. CHIP analysis demonstrated decreased FOXM1 binding to their promoters. Western blotting confirmed decreased expression, and increased expression of CDK inhibitor p21, a CKS1 target. In cells with TRPM2 deletion, cell cycle progression to S and G2/M phases was reduced after treatment with doxorubicin. RNA sequencing also identified decreased DNA repair proteins in cells with TRPM2 deletion after doxorubicin treatment, and DNA damage was increased. Wild type TRPM2 but not Ca2+-impermeable mutant E960D, restored live cell number and reconstituted expression of E2F1, FOXM1, and cell cycle/DNA repair proteins. FOXM1 expression alone restored viability. TRPM2 is a potential therapeutic target to reduce tumor proliferation and increase doxorubicin sensitivity through modulation of FOXM1, E2F1, and cell cycle/DNA repair proteins.

ORGANISM(S): Homo sapiens

PROVIDER: GSE197243 | GEO | 2022/02/25

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Similar Datasets

The human ion channel TRPM2 modulates migration and invasion in neuroblastoma through regulation of integrin expression

Project description:Transient receptor potential channel TRPM2 is highly expressed in many cancers and involved in regulation of key physiological processes including mitochondrial function, bioenergetics, and oxidative stress. In Stage 4 non-MYCN amplified neuroblastoma patients, high TRPM2 expression is associated with worse outcome. Here, neuroblastoma cells with high TRPM2 expression demonstrated increased migration and invasion capability. RNA sequencing, RT-qPCR, and Western blotting demonstrated that the mechanism involved significantly greater expression of integrins α1, αv, β1, and β5 in cells with high TRPM2 expression. Transcription factors HIF-1α, E2F1, and FOXM1, which bind promoter/enhancer regions of these integrins, were increased in cells with high TRPM2 expression. Subcellular fractionation confirmed high levels of α1, αv, and β1 membrane localization and co-immunoprecipitation confirmed the presence of α1β1, αvβ1, and αvβ5 complexes. Inhibitors of α1β1, αvβ1, and αvβ5 complexes significantly reduced migration and invasion in cells highly expressing TRPM2, confirming their functional role. Increased pAktSer473 and pERKThr202/Tyr204, which promote migration through mechanisms including integrin activation, were found in cells highly expressing TRPM2. TRPM2 promotes migration and invasion in neuroblastoma cells highly expressing TRPM2 through modulation of integrins together with enhancing cell survival, negatively affecting patient outcome and providing the rationale for TRPM2 inhibition in anti-neoplastic therapy.

2022-05-27 | GSE203660 | GEO

The human ion channel TRPM2 modulates cell survival in neuroblastoma through E2F1 and FOXM1

Project description:The human ion channel TRPM2 modulates cell survival in neuroblastoma through E2F1 and FOXM1

| PRJNA809423 | ENA

Identification of cell cycle-regulated genes periodically expressed in U2OS cells and their regulation by FOXM1 and E2F transcription factors

Project description:We identified the cell cycle-regulated mRNA transcripts genome-wide in the osteosarcoma derived U2OS cell line. This resulted in 2,140 transcripts mapping to 1,871 unique cell cycle-regulated genes that show periodic oscillations across multiple synchronous cell cycles. We identified genomic loci bound by the G2/M transcription factor FOXM1 by Chromatin immunoprecipitation followed by high-throughput sequencing (ChIP-seq) and associated these with cell cycle-regulated genes. FOXM1 was bound to cell cycle-regulated genes with peak expression in both S phase and G2/M phases. ChIP-seq genomic loci were shown to be responsive to FOXM1 using a real-time luciferase assay in live cells, showing that FOXM1 strongly activates promoters of G2/M phase genes and weakly activates those induced in S phase. Analysis of ChIP-seq data from a panel of cell cycle-transcription factors (E2F1, E2F4, E2F6, and GABPA) from ENCODE and ChIP-seq data for the DREAM complex, found that a set of core cell cycle genes regulated in both U2OS and HeLa cells are bound by multiple cell cycle transcription factors. These data identify the cell cycle regulated genes in a second cancer derived cell line and provide a comprehensive picture of the transcriptional regulatory systems controlling periodic gene expression in the human cell division cycle. Cell cycle-regulated gene expression identified from three double thymidine time courses and one thymidine nocodazole time course.

2013-10-11 | E-GEOD-50988 | biostudies-arrayexpress

Synergistic chemical combination for cell cycle restoration in senescent cells via FoxM1 and E2F1 activation

Project description:Cellular senescence wreaks defects in the aging organism. In this study, we co-treated two chemicals: rho-associated protein kinase (ROCK) inhibitor (Y-27632) and ataxia telangiectasia mutated (ATM) inhibitor (KU-60019) to overcome senescence more efficaciously, these two chemicals are already revealed to have senomorphic effects, suppressing senescent phenotypes. We find out that cocktail treatment synergistically alleviates diverse senescent phenotypes in senescent human dermal fibroblast cells. Through transcriptomic approach, FOXM1 and E2F1 are identified as key transcription factor of synergism to normalize senescent cells, of which activities are attenuated by senescence both in vitro and in vivo, but revitalized by co-treatment. Activation of FOXM1 precedes activation of E2F1 and mediates transcription of numerous genes totally shut off by cellular senescence, including E2F1. After that, E2F1 participates in transcriptomic change. For that, Cyclin-dependent kinase (CDKs), where are the confluences of both ATM-Chk2-CDKs and ROCK-Akt-CDKs signaling axes, are direct regulators of these transcription factors. Surprisingly, canonical aging-related CDK inhibitors have nothing to do with the onset of senomorphism. As the order of activations of FOXM1 and E2F1 that are in charge of G2 and G1 phase transition respectively, chemical combination releases senescent cell arrest in order of G2 then G1. Altogether, our data provide new insight into the way of amelioration of aging via pivotal cell cycle transcription factors, FOXM1 and E2F1, which are synergistically stimulated by inhibiting senescence-associated kinases, ATM and ROCK.

2022-06-22 | GSE178115 | GEO

Identification of cell cycle-regulated genes periodically expressed in U2OS cells and their regulation by FOXM1 and E2F transcription factors [Expression array]

2013-10-11 | GSE50988 | GEO

Characterization of an E2f1 acetylation-deficient knock-in mouse model by RNA-Seq profiling

Project description:Objective: The E2F1 transcription factor regulates the expression of genes involved in cell proliferation, apoptosis and other cellular processes. In addition to regulating transcription, a number of studies have revealed novel, transcription-independent functions for E2F1 in regulating DNA repair. E2F1 localizes to sites of DNA damage dependent on its phosphorylation at serine 31 (serine 29 in mice) by the ATM or ATR kinases. In addition to phosphorylation, E2F1 is also acetylated in response to DNA damage on three lysine residues (K117, K120, and K125 in human E2F1), however how acetylation regulates the DNA repair function of E2F1 is unknown. To study the functional significance of E2F1 acetylation in DNA repair in vivo, we generated a targeted mutant mouse line in which the three sites of E2F1 acetylation were mutated from lysine to arginine and named this allele E2f1 3KR. RNA-seq analysis was performed on wild type and E2f1 3KR mouse embryonic fibroblasts (MEFs), before and after treatment with the radiomimetic drug neocarzinostatin (NCS), to examine the impact of the 3KR mutation on global gene expression patterns.

2019-08-05 | GSE135360 | GEO

Genome-wide mapping of FOXM1 binding reveals co-binding with oestrogen receptor alpha in breast cancer cells (expression)

Project description:The forkhead transcription factor FOXM1 is a key regulator of the cell cycle and is overexpressed in cancer. Increased levels of FOXM1 are associated with both poor prognosis and oestrogen receptor (ERalpha) status in primary breast cancer. In this study, we map FOXM1 binding genome wide in both ERalpha-positive (MCF-7) and -negative (MDA-MB-231) breast cancer cells. We identify a common set of FOXM1 binding events at cell cycle-regulating genes, but in addition, in MCF-7 cells we find a high level of concordance with ERalpha-binding regions. FOXM1 binding at these co-binding sites is dependent on ERalpha binding, as depletion of ER protein levels reduced FOXM1 binding. FOXM1 interacts directly with both ERalpha co-activator CARM1 and is required for H3 arginine methylation at the ERalpha complex. Inhibition of FOXM1 activity with the ligand thiostrepton resulted in decreased FOXM1 binding at cca. 1400 sites genome wide and reduced expression of genes correlated with poor prognosis in ERalpha-positive tumour samples. These data demonstrate a novel role for the forkhead protein FOXM1 as an ERalpha cofactor and provide insight into the role of FOXM1 in ERalpha-positive breast cancer. MCF-7 cells were treated with either thiostrepton or DMSO for 6 hr. Each treatment was carried out in replicates of 6.

2013-01-07 | E-GEOD-40766 | biostudies-arrayexpress

Genome-wide mapping of FOXM1 binding reveals co-binding with oestrogen receptor alpha in breast cancer cells (ChIP-seq)

Project description:The forkhead transcription factor FOXM1 is a key regulator of the cell cycle and is overexpressed in cancer. Increased levels of FOXM1 are associated with both poor prognosis and oestrogen receptor (ERalpha) status in primary breast cancer. In this study, we map FOXM1 binding genome wide in both ERalpha-positive (MCF-7) and -negative (MDA-MB-231) breast cancer cells. We identify a common set of FOXM1 binding events at cell cycle-regulating genes, but in addition, in MCF-7 cells we find a high level of concordance with ERalpha-binding regions. FOXM1 binding at these co-binding sites is dependent on ERalpha binding, as depletion of ER protein levels reduced FOXM1 binding. FOXM1 interacts directly with both ERalpha co-activator CARM1 and is required for H3 arginine methylation at the ERalpha complex. Inhibition of FOXM1 activity with the ligand thiostrepton resulted in decreased FOXM1 binding at cca. 1400 sites genome wide and reduced expression of genes correlated with poor prognosis in ERalpha-positive tumour samples. These data demonstrate a novel role for the forkhead protein FOXM1 as an ERalpha cofactor and provide insight into the role of FOXM1 in ERalpha-positive breast cancer. The FOXM1-binding sites were mapped by ChIP-Seq in MCF-7 and MDA-MB-231 cells. Cells were treated either with thiostrepton, a FOXM1 inhibitor, or with DMSO (as control). Four replicates were performed in MCF7 cells and two replicates in MDA-MB-231 cells.

2013-01-07 | E-GEOD-40762 | biostudies-arrayexpress

Synergistic chemical combination for cell cycle restoration in senescent cells via FoxM1 and E2F1 activation

Project description:Synergistic chemical combination for cell cycle restoration in senescent cells via FoxM1 and E2F1 activation

| PRJNA737407 | ENA

Genome-wide mapping of FOXM1 binding sites

Project description:There are nearly fifty forkhead (FOX) transcription factors encoded in the human genome and due to sharing a common DNA binding domain, they are all thought to bind to similar DNA sequences. It is therefore unclear how these transcription factors are targeted to specific chromatin regions to elicit specific biological effects. Here we used ChIP-seq to investigate the genome-wide chromatin binding mechanisms used by the forkhead transcription factor FOXM1. In keeping with its previous association with cell cycle control, we demonstrate that FOXM1 binds and regulates a group of genes which are mainly involved in controlling late cell cycle events in the G2 and M phases. However, rather than being recruited through canonical RYAAAYA forkhead binding motifs, FOXM1 binding is directed via CHR elements. FOXM1 binds these elements through protein-protein interactions with the MMB transcriptional activator complex. Thus, we have uncovered a novel and unexpected mode of chromatin binding of a FOX transcription factor which allows it to specifically control cell cycle-dependent gene expression. Examination of FOXM1 binding sites in G2/M U2OS cells

2012-11-05 | E-GEOD-38170 | biostudies-arrayexpress

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

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