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Targeted Perturb-seq of regulators of the transcriptional network downstream of RAF-MAPK signaling [perturb_seq]

ABSTRACT: In this study we use a (targeted) perturb seq experiment in which we knock out 22 transcription factors downstream of MAPK signalling in order to reconstruct the transcriptional network downstream of RAF/MAPK signaling.

ORGANISM(S): Homo sapiens

PROVIDER: GSE250558 | GEO | 2024/01/13

REPOSITORIES: GEO

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Transcriptome analysis of pulsed activation of MAPK signaling in HEK-RAF-ER cells [RNA_seq_pulse_time_series]

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Lineage recording in human cerebral organoids (iTracer-perturb)

Project description:Induced pluripotent stem cell (iPSC) derived organoid systems provide models to study human organ development. Single-cell transcriptome sequencing enables highly-resolved descriptions of cell state heterogeneity within these systems and computational methods can reconstruct developmental trajectories. However, new approaches are needed to directly measure lineage relationships in these systems. Here we establish an inducible dual channel lineage recorder, iTracer, that couples reporter barcodes, inducible CRISPR/Cas9 scarring, and single-cell transcriptomics to analyze state and lineage relationships in iPSC-derived systems. This data set include the iTracer-perturb data of one cerebral organoid with simultaneous TSC2 perturbation and lineage recording.

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Raf/MEK signatures in zebrafish liver cells

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Comparative analysis of RAF depletion vs. MAPK inhibition

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| EGAS00001005743 | EGA

Raf/MEK signatures in zebrafish liver cells

Project description:An inducible oncogenic cell line ZFL-?Raf1-ER was established, in which oncogenic human Raf-1(?Raf1) can be activated in zebrafish liver cells by administration of 4-hydroxytamoxifen (4HT). Transcriptional profilling of the ZFL-?Raf1-ER cells with and without administration of 4HT and/or the MEK inhibitor U0126 defined the gene signatures transcriptionally regulated by hyperactive Raf/MEK/MAPK signaling in zebrafish liver cells. The ZFL-?Raf1-ER cells were cultured in 12-well plates till confluence. Cell were starved for 4h in plain medium and susequently treated with or without 1µM 4HT and/or 30µM U0126 for 12h. Biological triplications were taken for each condition.

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Changes in gene expression profile in mammalian cells upon Raf activation

Project description:Comparison of the changes in the gene expression profile of cells in which there is an activation of the Raf oncogene in the absence of any other extracellular signals Keywords: Response to oncogenic activation of the MAPK pathway

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Effects of kockouts of EGR1, FOS and their combination on the MAPK induced transcriptome [RNA_KO_clones]

Project description:In this study we used CRISPR/Cas9 to generate KO clones of the HEK-RAF-ER cell line that lack expression of EGR1, FOS and profiled the transcriptome after inducing RAF/MAPK signaling.

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Pan-Raf co-operates with PI3K-dependent signaling and critically contributes to myeloma cell survival independently of mutated RAS

Project description:The most common oncogenic mutations in multiple myeloma (MM) affect N- and K-RAS leading to constitutive activation of RAS-dependent signaling. Signal transduction via RAS, Raf and MAPK has been well described as a canonical pathway. In accordance with this assumption, we showed that the activity of the MEK/ERK module is strictly dependent on pan-Raf activity. However, inhibition of MEK/ERK has no or only minor effects on MM cell survival, whereas oncogenic Ras and pan-Raf critically contribute to survival of multiple myeloma cells. Therefore, we aimed to learn more about Raf-dependent but MEK-independent signaling effectors. We analyzed gene expression profiles in INA-6 cells after either pan-Raf inhibition with SB-590885 or MEK inhibition with PD-325901.

2016-11-21 | GSE75078 | GEO

A Non-Canonical Raf Function Is Required for Dorsal-Ventral Patterning in Drosophila Embryogenesis

Project description:Embryonic development requires the establishment of directional axes. In Drosophila, spatially discrete expression of transcription factors determines the anterior to posterior organization of the early embryo, while the Toll and TGF-beta signalling pathways determine the early dorsal to ventral pattern. Embryonic MAPK/ERK signaling contributes to both anterior to posterior patterning in the terminal regions and to dorsal to ventral patterning during oogenesis and embryonic stages. Here we describe a novel loss of function mutation in the Raf kinase gene, which leads to loss of ventral cell fates as seen through the loss of the ventral furrow, the absence of Dorsal/NF-kB nuclear localization, the absence of mesoderm determinants Twist and Snail, and the expansion of TGF-beta. Gene expression analysis showed cells adopting ectodermal fates similar to loss of Toll signaling. Our results combine novel mutants, live imaging, optogenetics and transcriptomics to establish a novel role for Raf, that appears to be independent of the MAPK cascade, in embryonic patterning.

2021-08-03 | GSE178187 | GEO

L-plastin Ser5 phosphorylation via RSKs, downstream effectors of the MAPK/ERK pathway, in (breast) cancer cells (and in vitro)

Project description:Deregulated cell migration and invasion, which are hallmarks of metastatic cancer cells, are correlated to structural and functional alterations of the actin cytoskeleton associated to a large panel of actin-binding proteins. Among these, the actin-bundling protein L-plastin, initially detected in leukocytes, is ectopically expressed in several solid tumours and is often considered as a metastatic marker. Phosphorylation of L-plastin on residue serine 5 (Ser5) has been shown to activate L-plastin and to be crucial for invasion and metastasis formation. Here, we investigate the signalling pathway leading to L-plastin Ser5 phosphorylation in four breast cancer cell lines. Whole genome microarray analysis comparing cell lines with different invasive capacities and corresponding L-plastin Ser5 phosphorylation levels revealed that genes of the MAPK/ERK pathway are differentially expressed. In line, in vitro kinase assays showed that MAPK/ERK pathway downstream kinases RSK1 and RSK2 are able to directly phosphorylate L-plastin on Ser5. In parallel to a knockdown approach, activation and inhibition studies of signalling molecules of the MAPK/ERK pathway, followed by computational modelling analysis, confirmed that RSK is an important activator of L-plastin in all four studied cell lines. Finally and rounding up our study, RSK knockdown significantly impaired migratory and invasive capacities of a selected invasive cell line, thus consolidating RSK as a promising therapeutic target in certain invasive carcinomas. Altogether, our data provide substantial evidence that the MAPK/ERK pathway is involved in L-plastin Ser5 phosphorylation in breast cancer cells with its downstream kinases RSK1 and RSK2 being able to directly phosphorylate L-plastin on Ser5.

2016-03-26 | E-MTAB-3487 | biostudies-arrayexpress

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