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Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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ERK Oscillation-Dependent Gene Expression Patterns and Deregulation By The Stress-Response

ABSTRACT: Studies were undertaken to determine whether oscillatory behavior in the extracellular signal regulated kinase (ERK) pathway results in unique gene regulation patterns. Microarray analysis was performed on three subcloned populations of human keratinocytes with distinct ERK signaling/oscillation phenotypes. Microarray analysis identified 45 genes that overlapped between 2 subclones with oscillation phenotypes but not in the subclone which is non-oscillatory. Transcription factor networks revealed a role for MED1 in mediating ERK oscillation-dependent gene expression, which was confirmed with Western blot analysis. Further experimentation confirmed a role for p38 in the mediation of MED1 phosphorylation and ERK oscillatory behavior. hTERT-immortalized normal human keratinocytes (provided by Dr. Jerry Shay, The University of Texas Southwestern Medical Center) were stably transfected with ERK1-green fluorescent protein chimera and stable subclones were isolated with distinct ERK activation/oscillation patterns: Clone #1 exhibits transient ERK activation with ligand activation but does not oscillate; Clone #2 exhibits persistent ERK oscillations that are dependent on ligand activation; and Clone #3 exhibits spontaneous ERK oscillations in the absence of ligand activation.

ORGANISM(S): Homo sapiens

SUBMITTER: Katrina Waters

PROVIDER: E-GEOD-55823 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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ERK Oscillation-Dependent Gene Expression Patterns and Deregulation By The Stress-Response

Project description:Studies were undertaken to determine whether oscillatory behavior in the extracellular signal regulated kinase (ERK) pathway results in unique gene regulation patterns. Microarray analysis was performed on three subcloned populations of human keratinocytes with distinct ERK signaling/oscillation phenotypes. Microarray analysis identified 45 genes that overlapped between 2 subclones with oscillation phenotypes but not in the subclone which is non-oscillatory. Transcription factor networks revealed a role for MED1 in mediating ERK oscillation-dependent gene expression, which was confirmed with Western blot analysis. Further experimentation confirmed a role for p38 in the mediation of MED1 phosphorylation and ERK oscillatory behavior.

2014-03-13 | GSE55823 | GEO

Context-dependent regulatory mechanisms control site-specific information processing within the MEK/ERK module

Project description:The impact of the cellular context and receptor type on the dynamics of phosphorylation cycles in signaling pathways are unclear. We employ an unbiased approach to identify network alterations that explain phosphorylation dynamics of the MEK/ERK module in response to hepatocyte growth factor or interleukin-6, comparing primary hepatocytes with the immortalized cell line HaCaT. By combining quantitative mass spectrometry with dynamic modeling, we elucidate the network structure in primary hepatocytes. For HaCaT, our model predicts additional dual feedback regulation, which we experimentally identify as DUSP6 and paxillin. Model analyses reveal switch-like ERK phospho-form distribution profiles in primary hepatocytes that are severely altered in HaCaT, explaining threshold, sensitivity and saturation behavior. We apply our approach to human hepatocellular carcinoma samples and identify, as predicted, elevated threonine-phosphorylated ERK levels in the tumor. This suggests that the prevalence of the mono-phosphorylated ERK rather than the doubly phosphorylated ERK is indicative for dysregulated proliferation.

2016-02-08 | PXD002460 | Pride

Phosphorylation ratio of pT vs pY ERK in MEK phosphorylation reaction determined by mass spectrometry

Project description:The purpose of this experiment is to determine the phosphorylation ratio of pT vs pY ERK present in ERK phosphorylation reaction by activated MEK E203K or MEK WildType. Aliquots were collected at 3 minutes 15 seconds, the time at which the mono-phosphorylated ERK is at its maximal. To determine the ratio between pT and pY ERK, synthetic AQUA peptides corresponding to the pY- and the pT-phosphorylated ERK were spiked into the sample. The two peptides have identical mass but they can be umabiguguously distinguished by their elution times and fragmentation spectra.

2020-01-14 | PXD016580 | Pride

Transcriptional Profiling Defines the Roles of ERK and p38 Kinases in Epidermal Keratinocytes

Project description:Epidermal keratinocytes respond to extracellular influences by activating cytoplasmic signal transduction pathways that change the transcriptional profiles of affected cells. To define responses to two such pathways, p38 and ERK, we used SB203580 and PD98059 as specific inhibitors, and identified the regulated genes after 1, 4, 24 and 48 hrs, using Affymetrix’ Hu133Av2 microarrays. Additionally, we compared genes specifically regulated by p38 and ERKs with those regulated by JNK and by all three pathways simultaneously. We find that the p38 pathway induces the expression of extracellular matrix and proliferation-associated genes, while suppressing microtubule-associated genes; the ERK pathway induces the expression of nuclear envelope and mRNA splicing proteins, while suppressing steroid synthesis and mitochondrial energy production enzymes. Both pathways promote epidermal differentiation and induce feedback inactivation of MAPK signaling. c-FOS, SRY and N-Myc appear to be the principal targets of the p38 pathway, Elk-1 SAP1 and HLH2 of ERK, while FREAC-4, ARNT and USF are common to both. The results for the first time comprehensively define the genes regulated by the p38 and ERK pathways in epidermal keratinocytes and suggest a list of targets potentially useful in therapeutic interventions. Human epidermal keratinocytes are grown in Keratinocyte Serum-Free Medium (Gibco) supplemented with 0.05 mg/ml bovine pituitary extract, 2.5 ng/ml epidermal growth factor, 0.09 mM CalCl2 and 1% penicillin/streptomycin (KGM). They are switched to Keratinocyte Serum Free-Media (Gibco) supplemented only with 1% penicillin/streptomycin (KBM) 24 h prior to commencing experiments. A set is left as controls, others treated with 5 uM JNK inhibitor SP600125, 15 uM p38 inhibitor SB203580, or 50 um ERK inhibitor PD98059. Timecourse of treated and parellel control samples over a 48 hr period was performed.

2013-09-05 | E-GEOD-50591 | biostudies-arrayexpress

Specific functions for ERK/MAPK signaling during PNS development

Project description:We have established functions of the stimulus dependent MAPKs, ERK1/2 and ERK5 in DRG, motor neuron, and Schwann cell development. Surprisingly, many aspects of early DRG and motor neuron development were found to be ERK1/2 independent and Erk5 deletion had no obvious effect on embryonic PNS. In contrast, Erk1/2 deletion in developing neural crest resulted in peripheral nerves that were devoid of Schwann cell progenitors, and deletion of Erk1/2 in Schwann cell precursors caused disrupted differentiation and marked hypomyelination of axons. The Schwann cell phenotypes are similar to those reported in neuregulin-1 and ErbB mutant mice and neuregulin effects could not be elicited in glial precursors lacking Erk1/2. ERK/MAPK regulation of myelination was specific to Schwann cells, as deletion in oligodendrocyte precursors did not impair myelin formation, but reduced precursor proliferation. Our data suggest a tight linkage between developmental functions of ERK/MAPK signaling and biological actions of specific RTK-activating factors. Microarray analysis on RNA extracts derived from E12.5 Erk1/2CKO(Wnt1) and wildtype DRGs

2010-10-16 | E-GEOD-24730 | biostudies-arrayexpress

Transcription profiling of Drosophila SL2 cells treated with E. coli with RNAi knock-down of Dsor1 or Gap1

Project description:Experiment was undertaken to compare the transcriptional response of SL2 cells to E. coli treatment with the response to modulated ERK/MAPK activity through RNAi of Dsor1 or Gap1.

2009-10-01 | E-MEXP-2145 | biostudies-arrayexpress

(AP-MS) Kinase Suppressor of RAS 1 (KSR1) maintains the transformed phenotype of BRAFV600E mutant human melanoma cells

Project description:KSR1 is a scaffolding protein for the RAS-RAF-MEK-ERK pathway, which is one of the most frequently altered pathways in human cancers. Previous results have shown that KSR1 has a critical role in mutant RAS mediated transformation. Here, we examined the role of KSR1 in mutant BRAF transformation. We used CRISPR/Cas9 to knock out KSR1 in a BRAFV600E transformed melanoma cell line. KSR1 loss produced a complex phenotype characterized by impaired proliferation, cell cycle defects, decreased transformation, decreased invasive migration, increased cellular senescence, and increased apoptosis. To decipher this phenotype, we used a combination of proteomic ERK substrate profiling, global protein expression profiling, and biochemical validation assays. The results suggest that KSR1 directs ERK to phosphorylate substrates that have a critical role in ensuring cell survival. The results further indicate that KSR1 loss induces the activation of p38 Mitogen- Activated Protein Kinase (MAPK) and subsequent cell cycle aberrations and senescence. In summary, KSR1 function plays a key role in oncogenic BRAF transformation.

2023-10-24 | PXD036261 | Pride

RNA-seq of canine MDCK epithelial cell line compared to cell line overexpressing ERK2 or cell line with conditional activation of the ERK pathway

Project description:Using RNA-seq and canine MDCK epithelial cells, we analyzed mRNA expression profiles of cells overexpressing ERK2 and cells where the ERK pathway was activated for 24 hrs. For this purpose, three cell lines were used: parental MDCK cells, MDCK cells overexpressing FLAG-ERK2 or MDCK cells expressing conditionally active Raf protein (ΔRaf1:ER). Activation of the ERK pathways was achieved by the addition of 4-Hydroxytamoxifen that converts ΔRaf1:ER protein to the active form and it subsequently activates the ERK pathway.

2022-10-01 | E-MTAB-12132 | biostudies-arrayexpress

Characterization of RAS/RAF/ERK signal cascade as a novel regulating factor in alpha-amanitin-induced liver injury

Project description:The well-known hepatotoxicity mechanism resulting from alpha-amanitin (-AMA) exposure arises from RNA polymerase II (RNAP II) inhibition. RNAP Ⅱ inhibition occurs through the dysregulation of mRNA synthesis. However, the signaling pathways in hepatocytes that arise from -AMA have not yet been fully elucidated. Here, we identified that the RAS/RAF/ERK signaling pathway was activated through quantitative phosphoproteomic and molecular biological analyses. Bioinformatics analysis showed that AMA exposure increased protein phosphorylation in a time-dependent AMA AMA exposure. In addition, phosphorylation increased not only the components of the ERK signaling pathway but also U2AF65 and SPF45, known splicing factors. Therefore, we propose a novel mechanism of -AMA as follows. The RAS/RAF/ERK signaling pathway involved in aberrant splicing events is activated by -AMA exposure followed by aberrant splicing events leading to cell death.

2023-03-11 | PXD035758 | Pride

Characterization of RAS/RAF/ERK signal cascade as a novel regulating factor in alpha-amanitin-induced liver injury

2023-03-11 | PXD035817 | Pride

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