Homo sapiens
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA124317 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:Microarray expression analysis to identify global changes in transcription in response to RAF inhibition. Genes under RAF control were identified in a panel of BRAFV600E tumor cells, following the short-term inhibition of RAF using a pan-RAF kinase inhibitor, PLX4032 (Plexxikon). For comparison with changes in gene expression in response to MEK inhibition using PD0325901 (Pfizer), the following array data was referenced: (http://www.ncbi.nlm.nih.gov/geo/ (accession no. GSE10086)). Cell lines growing in culture (n=5) were treated with the RAF inhibitor PLX4032 (250nM or 1000nM) or vehicle alone (0.1% DMSO) as control, for eight hours.
2010-07-18 | E-GEOD-20051 | biostudies-arrayexpress
Project description:<p>Dysregulated kinase activity drives oncogenic signalling, perturbs cellular homeostasis, and promotes tumour progression. Despite major success in targeting kinases therapeutically, the downstream consequences of kinase inhibition and the mechanisms underlying drug resistance remain incompletely understood. One of the most frequent oncogenic kinase mutations, BRAFV600E, constitutively activates the MAPK pathway and represents a major therapeutic target in melanoma and other cancers. However, the functional relevance of most phosphorylation events downstream of BRAF signalling is unknown, limiting mechanistic interpretation and rational therapeutic design.</p><p> Here, we established a global, multi-omic model of BRAF inhibition response in BRAFV600E-mutant melanoma cells by integrating time-resolved phosphoproteomics, biophysical PTM-proteomics, transcriptomics, and thermal proteome profiling. Our ultradeep phosphoproteomic analysis revealed widespread phosphorylation changes upon Dabrafenib treatment, while biophysical phosphoproteomics uncovered phosphorylation events associated with altered solubility and subcellular localisation, indicative of biomolecular condensation and nuclear reorganisation. Integration of these modalities into a network-based mechanistic model enabled the prioritisation of functionally relevant phosphorylation sites and kinases. Experimental validation confirmed CDK9, CLK3, and TNIK as key regulators of BRAFV600E signalling and as candidate targets for combinatorial inhibition strategies capable of re-sensitising resistant melanoma cells in a synthetic lethal manner.</p><p> The transcription factor ETV3 emerged from the network as a previously unrecognised effector of oncogenic BRAF signalling. Using phosphosite-specific biophysical data, imaging, and FRAP experiments, we demonstrated that ETV3 phosphorylation controls its DNA-binding kinetics. Functional assays combining ETV3 knockdown, metabolomics, and drug screening revealed that ETV3 modulates transcriptional and metabolic responses to BRAF inhibition, linking oncogenic signalling to metabolic rewiring.</p><p> Together, this study provides a comprehensive systems-level framework that connects phosphorylation dynamics to protein function and cellular phenotype, highlights ETV3 as a novel signalling node, and illustrates how multi-omic, site-resolved network models can reveal actionable mechanisms of kinase-driven oncogenesis.</p>
2025-12-09 | MTBLS7390 | MetaboLights
Project description:The RAF family kinases function in the RAS-ERK pathway to transmit signals from activated RAS to the downstream kinases MEK and ERK. This pathway regulates cell proliferation, differentiation, and survival enabling mutations in RAS and RAF to act as potent drivers of human cancers. Drugs targeting the prevalent oncogenic mutant BRAFV600E have shown great efficacy in the clinic but long-term effectiveness is limited by resistance mechanisms that often exploit the dimerization-dependent process by which RAF kinases are activated. Here, we investigated a proteolysis targeting chimera (PROTAC) approach to BRAF inhibition. The most effective PROTAC termed P4B displayed superior specificity and inhibitory properties relative to non-PROTAC controls in BRAFV600E cell lines. In addition, P4B displayed utility in two cell lines harboring alternate BRAF mutations that impart resistance to conventional BRAF inhibitors. This work provides a rationale for optimizing the drug-like properties of P4B to enable proof of concept studies in vivo.
2020-05-25 | GSE148500 | GEO
Project description:DNA Methylation Profiling of Melanoma Cell Lines
| PRJNA139413 | ENA
Project description:Gene expression profiling of immortalized human mesenchymal stem cells with hTERT/E6/E7 transfected MSCs. hTERT may change gene expression in MSCs. Goal was to determine the gene expressions of immortalized MSCs.
2010-09-25 | GSE24338 | GEO
Project description:Microarray expression analysis to identify global changes in transcription in response to RAF inhibition. Genes under RAF control were identified in a panel of BRAFV600E tumor cells, following the short-term inhibition of RAF using a pan-RAF kinase inhibitor, PLX4032 (Plexxikon). For comparison with changes in gene expression in response to MEK inhibition using PD0325901 (Pfizer), the following array data was referenced: (http://www.ncbi.nlm.nih.gov/geo/ (accession no. GSE10086)).
2010-07-18 | GSE20051 | GEO
Project description:Transcriptional profiling of human mesenchymal stem cells comparing normoxic MSCs cells with hypoxic MSCs cells. Hypoxia may inhibit senescence of MSCs during expansion. Goal was to determine the effects of hypoxia on global MSCs gene expression.
2011-02-19 | GSE20463 | GEO
Project description:Transcriptome of melanoma cell lines resistant to inhibition of the MAPK pathway.
| PRJNA389808 | ENA