Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Targeting mitochondrial translation overcomes multidrug resistance in FBXW7-deficient cells

ABSTRACT: FBXW7 is one of the most frequently mutated tumor suppressors, the deficiency of which has been associated with resistance to some anticancer therapies. Through bioinformatic analyses and genome-wide CRISPR screens, we here reveal that FBXW7 deficiency leads to multi-drug resistance (MDR), to a bigger extent than well-established MDR-drivers such as ABCB1. Proteomic data from FBXW7-deficient cells and human cancer samples identify the upregulation of mitochondrial function as a hallmark of FBXW7 deficiency, which has been previously linked to an increased resistance to chemotherapy. Accordingly, genetic or chemical targeting of mitochondria is preferentially toxic for FBXW7-deficient cells. For instance, targeting mitochondrial translation with the antibiotic Tigecycline efficiently kills FBXW7-deficient cells in vitro and in vivo, by a mechanism that involves activation of the Integrated Stress Response (ISR). Searching for additional drugs that overcome MDR in FBXW7-deficient cells, we found several targeted therapies such as Erlotinib, Dasatinib or Vemurafenib which unexpectedly also activate the ISR. Together, our study reveals that one of the most frequent mutations in cancer reduces the sensitivity to the vast majority of available therapies, and identifies a general principle to overcome such resistance.

INSTRUMENT(S): Q Exactive Plus

ORGANISM(S): Homo Sapiens (human) Mus Musculus (mouse)

TISSUE(S): Embryonic Stem Cell

SUBMITTER: Eduardo Zarzuela

LAB HEAD: Javier Muñoz

PROVIDER: PXD029981 | Pride | 2022-06-08

REPOSITORIES: Pride

ACCESS DATA

Json Xml

Similar Datasets

Mammalian CDC14 control differentiation from pluripotent cells by modulating UTF1 activity on bivalent promoters

Project description:CDC14 phosphatases are critical components of the cell cycle machinery that drives exit from mitosis in yeast. However, the two mammalian paralogs, CDC14A and CDC14B, are dispensable for cell cycle progression or exit, and their function remains unclear. By generating a double Cdc14a; Cdc14b-null mouse model, we report here that CDC14 phosphatases control cell differentiation in pluripotent cells and their absence results in deficient development of the neural system. Lack of CDC14 impairs neural differentiation from embryonic stem cells (ESCs) accompanied by deficient induction of genes controlled by bivalent promoters. During ESC differentiation, CDC14 directly dephosphorylates and destabilizes Undifferentiated embryonic Transcription Factor 1 (UTF1), a critical regulator of stemness. In the absence of CDC14, increased UTF1 levels prevent the firing of bivalent promoters, resulting in defective induction of the transcriptional programs required for differentiation. These results suggest that mammalian CDC14 phosphatases function during the terminal exit from the cell cycle by modulating the transition from the pluripotent to the differentiated chromatin state, at least partially by controlling chromatin dynamics and transcription in a UTF1-dependent manner.

2022-10-31 | PXD030296 | Pride

FBXW7

Project description:Purpose: FBXW7 is one of the most frequently mutated tumor suppressors, the deficiency of which has been associated with resistance to some anticancer therapies. Through bioinformatic analyses and genome-wide CRISPR screens, we here reveal that FBXW7 deficiency leads to multi-drug resistance (MDR), to a bigger extent than well-established MDR-drivers such as ABCB1. Proteomic data from FBXW7-deficient cells and human cancer samples identify the upregulation of mitochondrial function as a hallmark of FBXW7 deficiency, which has been previously linked to an increased resistance to chemotherapy. Accordingly, genetic or chemical targeting of mitochondria is preferentially toxic for FBXW7-deficient cells. For instance, targeting mitochondrial translation with the antibiotic Tigecycline efficiently kills FBXW7-deficient cells in vitro and in vivo, by a mechanism that involves activation of the Integrated Stress Response (ISR). Searching for additional drugs that overcome MDR in FBXW7-deficient cells, we found several targeted therapies such as Erlotinib, Dasatinib or Vemurafenib which unexpectedly also activate the ISR. Together, our study reveals that one of the most frequent mutations in cancer reduces the sensitivity to the vast majority of available therapies, and identifies a general principle to overcome such resistance. Methods: This study was performed in 2 groups of DLD1 cells with duplicate samples per group. Both control (Wild Type, WT) and experimental (FBXW7 -/-, KO) were exposed to Tigecycline (10µM). DMSO was used as a control for the treatment. After 24h, the RNA was extracted and the transcriptome was profiled with RNA-Sequencing (RNA-seq) analysis. Results: our study reveals that one of the most frequent mutations in cancer reduces the sensitivity to the vast majority of available therapies, and identifies a general principle to overcome such resistance.

2022-06-09 | GSE189499 | GEO

Regulated local synthesis of ribosomal proteins maintains ribosome function in axons

Project description:Ribosome assembly occurs mainly in the nucleolus yet recent studies have revealed robust enrichment and translation of mRNAs encoding many ribosomal proteins (RPs) in axons, far away from neuronal cell bodies. Here, we report a physical and functional interaction between locally synthesized RPs and ribosomes in the axon. We show that axonal RP translation is regulated through a novel sequence motif, CUIC, that forms an RNA-loop structure in the region immediately upstream of the initiation codon. Using imaging and subcellular proteomics techniques, we show that RPs synthesized in axons join axonal ribosomes in a nucleolus-independent fashion. Inhibition of axonal CUIC-regulated RP translation causes a significant decline in local translation activity and markedly reduces axon branching in the brain, revealing the physiological relevance of axonal RP synthesis in vivo. These results suggest that axonal translation supplies cytoplasmic RPs to maintain/modify local ribosomal function far from the nucleolus in neurons.

2019-12-09 | PXD015574 | Pride

TMTpro16plex Isobaric Labeling Reagents: Attaining New Sample Multiplexing Heights and New Cellular Proteome Depths in Quantitative Proteomics

Project description:Isobaric labeling empowers proteome-wide expression measurements simultaneously across multiple samples. Here, an expanded set of 16 isobaric reagents based on a proline backbone (TMTpro) is presented. These reagents have similar characteristics to existing TMT reagents but with increased fragmentation efficiency and signal. In a proteome-scale example dataset, we compared eight common cell lines with and without Torin1 treatment with three replicates, quantifying more than 8,800 proteins (mean of 7.5 peptides/protein) per replicate with an analysis time of only 67 min per proteome examined. Finally, we modified the powerful thermal stability assay to examine proteome-wide melting shifts after treatment with DMSO, 1 or 20 ��M staurosporine with five replicates. This new assay identified and dose-stratified the staurosporine binding to 228 cellular kinases in just one, 18-hr experiment. TMTpro reagents allow unprecedented complexity in experimental designs��all with basically no missing values across the 16 samples and no loss in quantitative integrity.

2020-03-19 | PXD016940 | Pride

TMTpro16plex Isobaric Labeling Reagents: Attaining New Sample Multiplexing Heights and New Cellular Proteome Depths in Quantitative Proteomics

Project description:Isobaric labeling empowers proteome-wide expression measurements simultaneously across multiple samples. Here, an expanded set of 16 isobaric reagents based on a proline backbone (TMTpro) is presented. These reagents have similar characteristics to existing TMT reagents but with increased fragmentation efficiency and signal. In a proteome-scale example dataset, we compared eight common cell lines with and without Torin1 treatment with three replicates, quantifying more than 8,800 proteins (mean of 7.5 peptides/protein) per replicate with an analysis time of only 67 min per proteome examined. Finally, we modified the powerful thermal stability assay to examine proteome-wide melting shifts after treatment with DMSO, 1 or 20 µM staurosporine with five replicates. This new assay identified and dose-stratified the staurosporine binding to 228 cellular kinases in just one, 18-hr experiment. TMTpro reagents allow unprecedented complexity in experimental designs—all with basically no missing values across the 16 samples and no loss in quantitative integrity.

2020-03-19 | PXD016491 | Pride

TMTpro16plex Isobaric Labeling Reagents: Attaining New Sample Multiplexing Heights and New Cellular Proteome Depths in Quantitative Proteomics

Project description:Isobaric labeling empowers proteome-wide expression measurements simultaneously across multiple samples. Here, an expanded set of 16 isobaric reagents based on a proline backbone (TMTpro) is presented. These reagents have similar characteristics to existing TMT reagents but with increased fragmentation efficiency and signal. In a proteome-scale example dataset, we compared eight common cell lines with and without Torin1 treatment with three replicates, quantifying more than 8,800 proteins (mean of 7.5 peptides/protein) per replicate with an analysis time of only 67 min per proteome examined. Finally, we modified the powerful thermal stability assay to examine proteome-wide melting shifts after treatment with DMSO, 1 or 20 µM staurosporine with five replicates. This new assay identified and dose-stratified the staurosporine binding to 228 cellular kinases in just one, 18-hr experiment. TMTpro reagents allow unprecedented complexity in experimental designs—all with basically no missing values across the 16 samples and no loss in quantitative integrity.

2020-03-19 | PXD014369 | Pride

Mig6 mediates adaptive and acquired resistance to ALK and ROS1 fusion kinase inhibition through feedback activation of EGFR: Cuto28

Project description:ALK and ROS1 fusions defines subsets of lung adenocarcinoma. Although ALK/ROS1 inhibitors improved therapeutic outcome of patients harboring those oncogenic fusions, complete responses were rare, and resistance eventually develops from the residual tumor. To under the mechanisms contributing to residual tumor formation, we performed phosphoproteomics to explore the signaling adaption shortly after ALK/ROS1 inhibition. We found the phosphorylation of Mig6, a potent inhibitor for EGFR, was decreased following ALK/ROS1 inhibition, impairing Mig6 binding and inhibition on EGFR. Furthermore, Mig6 mRNA and protein levels were decreased rapidly by ALK/ROS1 inhibitors, potentiating EGFR activity to support cell survival. We also uncovered a novel mechanism mediated by Mig6 to regulate EGFR activity without impacting EGFR phosphorylation, but rather altering signaling adaptor SHC1 binding to EGFR. Mig6 expression was also lost following long-term exposure to ALK/ROS1 inhibitors to support EGFR-mediated acquired resistance. Finally, a Mig6 EGFR-binding domain truncation mutation was identified in a patient-derived ROS1 cell line, rendering its resistance to ROS1 inhibitors but sensitivity to HER family inhibitors. Our work established a rationale to evaluate combinations of ALK/ROS1 and EGFR inhibitors to limit residual tumor formation, therefore preventing or delaying subsequent resistance emergence.

2023-09-12 | PXD036771 | Pride

Mig6 mediates adaptive and acquired resistance to ALK and ROS1 fusion kinase inhibition through feedback activation of EGFR: H3122

2023-09-12 | PXD036772 | Pride

Gene expression profiling in the reprogramming process

Project description:It remains unclear how the ectopic expression of defined transcription factors induces dynamic changes in gene expression profiles that establish a pluripotent state during direct cell reprogramming. In the present study, we first identified a temporal gene expression program during the reprogramming process. Promoter analyses then predicted the role of two forkhead box transcription factors, Foxd1 and Foxo1, as mediators of the gene expression program. Knockdown of Foxd1 or Foxo1 reduced the number of induced pluripotent stem cells (iPSCs). The knockout of Foxd1 prevented the downstream transcription program, including the expression of reprogramming marker genes. Interestingly, the expression level of Foxd1 was also transiently increased in a small population of cells in the middle stage of reprogramming. The presence or absence of Foxd1 expression in this stage was correlated with a future cell fate as iPSCs or non-reprogrammed cells. These results suggest that Foxd1 is a mediator and indicator of the successful progression of the gene expression program in cell reprogramming. Mouse embryonic fibroblasts (MEFs) were infected with retroviruses encoding either the four transcription factors (Oct4, Sox2, Klf4 and c-Myc) or GFP (control) at day 0 and sampled on the indicated days. Two replicates each.

2014-01-11 | E-GEOD-38509 | biostudies-arrayexpress

Genome-wide characterization of HSF1 binding in human WT and FBXW7 KO colon cancer cells under basal conditions and upon heat shock

Project description:FBXW7 modulates stress response by post-translational modification of HSF1 HSF1 orchestrates the heat-shock response upon exposure to heat stress and activates a transcriptional program vital for cancer cells. In this study we assayed for genome-wide localization of HSF1 enrichment in the HCT116 FBXW7 KO colon cells and their wild type counterpart in untreated cells and upon heat shock. These results revealed that accumulation of nuclear HSF1 in FBXW7 KO cells results in rewiring of the HSF1 transcriptional program. Five million cells were used for the ChIP and precipitated using 5 micrograms of antibody (cell signaling, 4356) against human HSF1

2015-02-20 | E-GEOD-57398 | 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