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Hyperactive mTOR and MNK1 phosphorylation of eIF4E confer tamoxifen resistance and estrogen independence through selective mRNA translation reprogramming

ABSTRACT: Hyperactive mTOR and MNK1 phosphorylation of eIF4E confer tamoxifen resistance and estrogen independence through selective mRNA translation reprogramming

PROVIDER: PRJNA420692 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR6337450.fastq.gz	Fastqsanger.gz
	SRR6337460.fastq.gz	Fastqsanger.gz
	SRR6337470.fastq.gz	Fastqsanger.gz
	SRR6337480.fastq.gz	Fastqsanger.gz
	SRR6337490.fastq.gz	Fastqsanger.gz

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Hyperactive mTOR and MNK1 phosphorylation of eIF4E confer tamoxifen resistance and estrogen independence through selective mRNA translation reprogramming

Project description:Tamoxifen resistant translational reprogramming is shown to be mediated by increased expression of eIF4E and its increased availability by hyperactive mTOR, and to require phosphorylation of eIF4E at Ser209 by increased MNK activity.

2017-12-21 | GSE107590 | GEO

Hyperactive mTOR and MNK1 phosphorylation of eIF4E confer tamoxifen resistance and estrogen independence through selective mRNA translation reprogramming.

Project description:The majority of breast cancers expresses the estrogen receptor (ER+) and is treated with anti-estrogen therapies, particularly tamoxifen in premenopausal women. However, tamoxifen resistance is responsible for a large proportion of breast cancer deaths. Using small molecule inhibitors, phospho-mimetic proteins, tamoxifen-sensitive and tamoxifen-resistant breast cancer cells, a tamoxifen-resistant patient-derived xenograft model, patient tumor tissues, and genome-wide transcription and translation studies, we show that tamoxifen resistance involves selective mRNA translational reprogramming to an anti-estrogen state by Runx2 and other mRNAs. Tamoxifen-resistant translational reprogramming is shown to be mediated by increased expression of eIF4E and its increased availability by hyperactive mTOR and to require phosphorylation of eIF4E at Ser209 by increased MNK activity. Resensitization to tamoxifen is restored only by reducing eIF4E expression or mTOR activity and also blocking MNK1 phosphorylation of eIF4E. mRNAs specifically translationally up-regulated with tamoxifen resistance include Runx2, which inhibits ER signaling and estrogen responses and promotes breast cancer metastasis. Silencing Runx2 significantly restores tamoxifen sensitivity. Tamoxifen-resistant but not tamoxifen-sensitive patient ER+ breast cancer specimens also demonstrate strongly increased MNK phosphorylation of eIF4E. eIF4E levels, availability, and phosphorylation therefore promote tamoxifen resistance in ER+ breast cancer through selective mRNA translational reprogramming.

| S-EPMC5769768 | biostudies-literature

Discovery of a novel plant eIF4E-binding protein: Conserved Binding of eIF4E 1 (CBE1)

Project description:Regulation of translation initiation is accomplished in diverse eukaryotes through proteins which bind to the mRNA cap-binding protein, eIF4E, and either prevent its association with eIF4G or form repressive mRNPs which exclude the translation machinery. Such mechanisms in plants, and even the presence of eIF4E-interacting proteins outside of eIF4G (and the plant-specific isoform eIFiso4G, which binds eIFiso4E) which operate in a gene regulatory manner are not known. Here we describe the Conserved Binding of eIF4E 1 (CBE1), a plant-specific protein with an evolutionarily conserved eIF4E binding motif. This protein binds eIF4E or eIFiso4E in vitro to form cap-binding complexes, and is found as a constituent of cap-binding complexes in vivo in an eIF4E-dependent manner. Mutants lacking CBE1 show dysregulation of cell cycle related transcripts, accumulating higher levels relative to wild-type plants of mRNAs encoding proteins involved in mitotic processes. These findings support CBE1 as a plant protein with the capability to form cap-binding complexes with the potential for gene regulatory activity.

2018-09-26 | GSE114363 | GEO

MDA-MB-231 eIF4E RIP-CHIP

Project description:Cytoplasmic RNA bound to eIF4E was pulled down from MDA-MB-231 cells to determine the influence of radiation on eIF4E mRNA binding 4 samples were analyzed with 3 biological replicates

2012-06-14 | E-GEOD-36179 | biostudies-arrayexpress

Proteome profiling followng targeting eIF4E

Project description:Here we have compared the impact of loss the protein synthesis initiation factor eIF4e in non samll cell lung cancer cells. Expression of eIF4E was targeted by an eIF4E siRNA or by expressiojn of eIF4E-dTAG construct allowing degradation of eIF4e-dTAG with the heterobifunctional dTAGv-1 small molecule. Proteomes were profiled following 72 hr exposure of the four H1299 eIF4E-dTAG clones (C2-2, C3-1, N2-1 and N3-2) to 0.5 microM dTAGV-1 or H1299 parent cells transfected with 1 microg eIF4E siRNA (siTOOLS, Planegg, Germany) using Lipofectamine 3000 transfection reagent (Fisher Scientific, cat#L3000008).

2025-05-07 | PXD057122 | Pride

MDA-MB-231 eIF4E RIP-CHIP

Project description:Cytoplasmic RNA bound to eIF4E was pulled down from MDA-MB-231 cells to determine the influence of radiation on eIF4E mRNA binding

2012-06-15 | GSE36179 | GEO

eIF4E phosphorylation promotes tumorigenesis and is associated with prostate cancer progression

Project description:Translational regulation plays a critical role in cell growth and proliferation, and its dysregulation results in cancer. Aberrant expression of the mRNA 5’cap-binding protein, eIF4E, has been implicated in cancer development and progression. eIF4E activity is promoted by phosphorylation. Here we show that “knock-in” mice in which eIF4E cannot be phosphorylated are resistant to tumorigenesis in a prostate cancer model. We identify multiple candidate genes involved in the resistance to oncogenic transformation. Importantly, phosphorylation of eIF4E is increased in hormone-refractory prostate cancer, the deadliest stage of the disease. Our results highlight eIF4E phosphorylation as a critical event in tumorigenesis. Comaparison of total RNA and polysomal RNA from mouse embryo fibroblasts derived from WT and eIF4E-KI (non phosphorylatable eIF4E) mice

2010-08-17 | E-GEOD-17451 | biostudies-arrayexpress

Overexpression of eukaryotic translation initiation factor, eIF4E confers tamoxifen resistance in breast cancer via the ERα/FOXM1 axis

Project description:Overexpression of eukaryotic translation initiation factor, eIF4E confers tamoxifen resistance in breast cancer via the ERα/FOXM1 axis

| PRJNA549272 | ENA

Redefining the role of eIF4E dose in development, cancer, and protein synthesis

Project description:eIF4E, the major cap-binding protein, has long been considered limiting for translating the mammalian genome. However, the requirement for eIF4E dose at an organismal level remains unexplored. By generating an Eif4e haploinsufficient mouse, we surprisingly found that 50% reduction in eIF4E, while compatible with normal development and global protein synthesis, significantly impeded cellular transformation and tumorigenesis. Genome-wide translational profiling uncovered a translational program induced by oncogenic transformation and revealed a critical role for eIF4E dose specifically in translating a network of mRNAs enriched for a unique 5’UTR signature. In particular, we demonstrate that eIF4E dose is essential for translating mRNAs regulating reactive oxygen species (ROS) that fuel transformation and cancer cell survival in vivo. Therefore, mammalian cells have evolved surplus eIF4E levels that cancer cells hijack to drive a translational program supporting tumorigenesis Total cellular RNA and high MW polysome associated RNA were isolated from matched untransformed and transformed WT and Eif4e+/- MEFs for analysis on Affymetrix Mouse Gene 1.0 ST arrays. The difference in log2 RMA intensity between matched polysomal RNA and total RNA was taken to quantify translational efficiency (TE).

2015-07-01 | E-GEOD-68238 | biostudies-arrayexpress

eIF4E hypersensitive mRNA translation is characterized by long and structured untranslated regions

Project description:Combining a genetic and pharmacological approach, we modulated eIF4E activity across its physiological activity range and identified subsets of genes whose translation was either hypo- or hyper- sensitive to eIF4E activity changes. eIF4E hypersensitive genes had longer 5'UTRs with higher GC content; and longer 3'UTRs with lower GC content and a higher density of unique microRNA target sites. Proliferation related genes were enriched among eIF4E hypersensitive genes; and consistent with this, decreasing eIF4E activity inhibited cell cycle transit. Our findings provide genome wide insights into the properties of mRNAs under translational control across the physiological range of eIF4E activity. NIH 3T3 derivatives genetically altered to induce eIF4E when treated with mifepristone and a non-inducible control NIH 3T3 derivative were cultured with or without treatment with mifepristone and varying doses of a pharmacological eIF4E inhibiting agent, 4Ei-1 (0 Î¼M, 10 Î¼M, 50 Î¼M, 100 Î¼M, 200 Î¼M). Total RNA and polyribosome RNA were isolated after 4h of treatment. Three replicates of each experimental group were completed. In addition, three replicates of the inducible cell line treated with less potent analog to the inhibiting agent, 4Ei-4, were completed to probe for non-specific drug effects.

2015-12-31 | E-GEOD-56072 | biostudies-arrayexpress

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