Ontology highlight
ABSTRACT:
PROVIDER: PRJNA704901 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR13783234_1.fastq.gz | Fastqsanger.gz | |||
| SRR13783234_2.fastq.gz | Fastqsanger.gz | |||
| SRR13783235_1.fastq.gz | Fastqsanger.gz | |||
| SRR13783235_2.fastq.gz | Fastqsanger.gz | |||
| SRR13783236_1.fastq.gz | Fastqsanger.gz |
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Project description:Acquired resistance to MAPK inhibitors limits the clinical efficacy in melanoma treatment. We and others have recently shown that BRAF inhibitors (BRAFi)-resistant melanoma cells can develop a dependency on the therapeutic drugs to which they have acquired resistance, creating a vulnerability for these cells that can potentially be exploited in cancer treatment. In drug addicted melanoma cells, it was shown that this induction of cell death was preceded by a specific ERK2-dependent phenotype switch, however, the underlying molecular mechanisms are largely lacking. To increase the molecular understanding of this drug dependency, we applied a mass spectrometry-based proteomic approach on BRAFi-resistant BRAFMUT 451Lu cells, in which ERK1, ERK2 and JUNB were silenced separately using CRISPR–Cas9. Inactivation of ERK2 and, to a lesser extent, JUNB prevents drug addiction in these melanoma cell while, conversely, knock out of ERK1 fails to reverse this phenotype, showing a response similar to control cells. Our analysis reveals that ERK2 and JUNB share comparable proteome responses dominated by reactivation of cell division. Importantly, we find that EMT activation in drug addicted melanoma cells upon drug withdrawal is affected by silencing ERK2 but not ERK1. Moreover, transcription factor (regulator) enrichment shows that PIR acts as an effector of ERK2 and phosphoproteome analysis reveals that silencing of ERK2 but not ERK1 leads to amplification of GSK3 kinase activity. Our results depict possible mechanisms of drug addiction in melanoma, which may provide a guide for strategies in drug-resistant melanoma.
2022-02-17 | PXD026557 | Pride
Project description:Extracellular signal regulated kinases, ERK1 and ERK2 are often considered as redundant due to their high homology, large number of overlapping substrates, and ability to substitute for each other in genetically engineered mouse models. We have investigated the individual contribution of ERK1 and ERK2 to the survival of human melanoma cell lines driven by oncogenic BRAF. ERK2, but not ERK1 activity, was crucial to drive survival and maintain transcriptional output of the MAPK pathway. Furthermore, we found that ERK2 DEF-domain interactions were crucial for transcriptional regulation and survival in some cells, but not in others, whereas ERK2-substrate interactions at the D-docking motif were largely dispensable. We used microarrays to examine the global impact of gene expression by imhibiting different nodes of MAPK pathway.
2018-12-31 | GSE57721 | GEO
Project description:FDA-approved BRAF inhibitors produce high response rates and improve overall survival in patients with BRAF V600E/K mutant melanoma, but are linked to pathologies associated with paradoxical ERK1/2 activation in wild-type BRAF cells. To overcome this limitation, a next-generation paradox breaking RAF inhibitor (PLX8394) has been designed. Here we show that by using a quantitative reporter assay, PLX8394 rapidly suppressed ERK1/2 reporter activity and growth of mutant BRAF melanoma xenografts. Ex vivo treatment of xenografts and use of a patient-derived explant system (PDeX) revealed that PLX8394 suppressed ERK1/2 signaling and elicited apoptosis more effectively than the FDA-approved BRAF inhibitor, vemurafenib. Furthermore, PLX8394 was efficacious against vemurafenib-resistant BRAF splice-variant expressing tumors and reduced splice-variant homodimerization. Importantly, PLX8394 did not induce paradoxical activation of ERK1/2 in wild-type BRAF cell lines or PDeX. Continued in vivo dosing of xenografts with PLX8394 led to the development of acquired resistance via ERK1/2 reactivation through heterogeneous mechanisms; however, resistant cells were found to have differential sensitivity to ERK1/2 inhibitor. These findings highlight the efficacy of a paradox-breaking selective BRAF inhibitor and the use of PDeX system to test efficacy of therapeutic agents.
2022-01-24 | GSE180567 | GEO
Project description:ERK1 and ERK2 MAPKs are intensively studied signaling proteins that are involved in numerous cellular processes and signaling networks. However, their specific functions in embryonic development remain elusive. The upstream activation pathways for ERK1 and ERK2 are considered to be highly similar, and also many of their downstream targets are considered as common, but still relatively few in vivo downstream targets of these kinases have been identified conclusively. Recent mice studies indicate distinct roles for both ERKs in cellular proliferation, oncogenic transformation and development. <br><br>Microarray experiments were performed to compare morpholino mediated knockdown of ERK1 versus ERK2 in zebrafish development. These two conditions were compared to a standard control morpholino condition. To exclude possible effects of the control morpholino at a transcriptional level, we also performed the transciptome-analysis of the control morpholino, to an injection control (injection with phenol red).
2008-01-01 | E-MEXP-1163 | biostudies-arrayexpress
Project description:This dataset consists of 11 raw MS files and associated peak lists and result files, acquired on an Orbitrap Fusion mass spectrometer operated in Data Dependent Acquisition mode. The files are associated with a manuscript submitted for publication by Thibault Houles et al. titled: CDK12 is hyperactivated and a prime synthetic-lethal target in BRAF-mutated melanoma. The manuscript defines the proximity interactome of ERK1 and ERK2 kinases in HEK293 cells, and the consequences of ERK1/2-mediated CDK12 phosphorylation. Experiments are proximity-dependent biotinylation (BioID), all performed in biological triplicates with associated negative controls. Philippe Roux is the corresponding author of the manuscript philippe.roux at umontreal.ca.
2021-08-17 | MSV000087994 | MassIVE
Project description:Activation of ERK1 and ERK2 is essential in regulation of a wide variety of cellular and physiological processes. In native inner medullary collecting ducts, vasopressin (AVP) working through the V2 subtype vasopressin receptor (V2R)-mediated activation of Gαs, inhibits ERK1 and ERK2 activity. However, it has been reported that V2R can signal independently of Gαs through the activation of β-arrestin, which activates ERK1 and ERK2. Vaptans, V2R antagonists that function as so-called “inverse agonists”, have the potential of promoting cell proliferation via β-arrestin-dependent ERK activation. Here we use the mpkCCD cell line which natively expresses V2R to investigate the effects of AVP, the V2-selective analog dDAVP, and tolvaptan on ERK1 and ERK2 phosphorylation and activation. We demonstrated that ERK1 and ERK2 phosphorylation in mpkCCD cells was significantly reduced by either AVP or dDAVP, in contrast to the increases seen in non-collecting duct cells overexpressing V2R. We also found that tolvaptan has a strong effect to increase ERK1 and ERK2 phosphorylation in the presence of dDAVP and that the tolvaptan effect to increase ERK1 and ERK2 phosphorylation is absent in PKA-null mpkCCD cells. Thus, it appears that the tolvaptan effect to increase ERK activation is PKA-dependent and, therefore, not mediated by the β-arrestin pathway. Overall, the studies show that AVP decreases and that tolvaptan increases ERK1 and ERK2 activation in cells expressing V2R at endogenous levels, and provide no evidence for a role for β-arrestin in the regulation of ERK1 and ERK2 activity.
2023-11-17 | GSE243773 | GEO
Project description:Activation of ERK1 and ERK2 is essential in regulation of a wide variety of cellular and physiological processes. In native inner medullary collecting ducts, vasopressin (AVP) working through the V2 subtype vasopressin receptor (V2R)-mediated activation of Gαs, inhibits ERK1 and ERK2 activity. However, it has been reported that V2R can signal independently of Gαs through the activation of β-arrestin, which activates ERK1 and ERK2. Vaptans, V2R antagonists that function as so-called “inverse agonists”, have the potential of promoting cell proliferation via β-arrestin-dependent ERK activation. Here we use the mpkCCD cell line which natively expresses V2R to investigate the effects of AVP, the V2-selective analog dDAVP, and tolvaptan on ERK1 and ERK2 phosphorylation and activation. We demonstrated that ERK1 and ERK2 phosphorylation in mpkCCD cells was significantly reduced by either AVP or dDAVP, in contrast to the increases seen in non-collecting duct cells overexpressing V2R. We also found that tolvaptan has a strong effect to increase ERK1 and ERK2 phosphorylation in the presence of dDAVP and that the tolvaptan effect to increase ERK1 and ERK2 phosphorylation is absent in PKA-null mpkCCD cells. Thus, it appears that the tolvaptan effect to increase ERK activation is PKA-dependent and, therefore, not mediated by the β-arrestin pathway. Overall, the studies show that AVP decreases and that tolvaptan increases ERK1 and ERK2 activation in cells expressing V2R at endogenous levels, and provide no evidence for a role for β-arrestin in the regulation of ERK1 and ERK2 activity.
2024-09-22 | GSE235936 | GEO
Project description:The analysis examined the effects of a global ERK1 and/or tamoxifen-inducible, hepatocyte-specific ERK2 knockout on the liver transcriptome. Transcriptomes from the livers with a ERK1/2 double knockout were compared to the livers of mice with an ERK1 or ERK2 knockout.
2021-08-13 | GSE181803 | GEO
Project description:Melanoma cell lines were assessed for differences in gene expression patterns between the lines sensitive and resistant to BRAF and MEK inhibitor drugs. 22 BRAF-mutant melanoma cell lines were assessed for response to BRAF and MEK inhibitors in a 3 day drug treatment dose response assay. Based on the IC50, 18 lines were found to be responsive to BRAF or MEK inhibition and 4 were resistant. Normalised gene expression data generated from experimental replicate affymetrix arrays was assessed to identify differential patterns of inherent gene expression between the cell lines grouped as drug-responsive or drug-resistant. This were used to idenify specific candidate genes and pathways associated with inherent BRAF/MEK inhibitor drug resistance in melanoma cells.
2015-08-26 | E-GEOD-45558 | biostudies-arrayexpress
Project description:Angiogenesis is a complex process orchestrated by both growth factors and cell adhesion to the extracellular matrix and is initiated by focal degradation of the vascular basement membrane with subsequent migration and proliferation of endothelial cells (EC). The Ras/Raf/MEK/ERK pathway is critical for EC function during angiogensis. Although in vitro studies implicate ERK1 and ERK2 in EC survival, their precise role in EC function in vivo remains poorly defined. Cre/loxP technology was used to inactivate Erk1 and Erk2 in EC during murine development, resulting in embryonic lethality due to a drastic reduction in angiogenesis. The angiogenic defect was linked to diminished EC proliferation and migration, but not to increased cell apoptosis. Expression of key cell cycle regulators was diminished in the double knockout cells. In addition, both Paxillin and Focal Adhesion Kinase were expressed at lower levels and failed to correctly localize to the cell membrane in EC lacking Erk1 and Erk2, leading to defects in the organization of the cytoskeleton and in cell motility. The results demonstrate that ERK1 and ERK2 coordinate cell proliferation and migration during angiogenesis. Lentivirus infected cells to generate ERK1/2 WT and ERK1/2 DKO endothelial cells were cultured, RNA was extracted and Affymetrix gene expression arrays were performed.
2010-07-30 | E-GEOD-16967 | biostudies-arrayexpress