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EIF4E phosphorylation promotes tumorigenesis and is associated with prostate cancer progression

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE17451 | GEO | 2010/08/17

SECONDARY ACCESSION(S): PRJNA118901

REPOSITORIES: GEO

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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

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

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

2015-07-01 | GSE68238 | GEO

Project description:Eukaryotic translation initiation factor 4E (eIF4E)–binding protein 1 (4E-BP1) inhibits cap-dependent translation in eukaryotes by competing with eIF4G for an interaction with eIF4E. Phos-phorylation at Ser-83 of 4E-BP1 occurs during mitosis through the activity of cyclin-dependent kinase 1 (CDK1)/cyclin B rather than through canonical mTOR kinase activity. Here, we investi-gated the interaction of eIF4E with 4E-BP1 or eIF4G during interphase and mitosis. We observed that 4E-BP1 and eIF4G bind eIF4E at similar levels during interphase and mitosis. The most highly phosphorylated mitotic 4E-BP1 isoform (δ) did not interact with eIF4E, whereas a distinct 4E-BP1 phospho-isoform, EB-γ—phosphorylated at Thr-70, Ser-83, and Ser-101—bound to eIF4E during mitosis. Two-dimensional gel electropho-retic analysis corroborated the identity of the phosphorylation marks on the eIF4E-bound 4E-BP1 isoforms and uncovered a population of phosphorylated 4E-BP1 molecules lacking Thr-37/Thr-46–priming phosphorylation. Moreover, proximity ligation assays for phospho–4E-BP1 and eIF4E revealed different in situ interactions during interphase and mitosis. The eIF4E:eIF4G interaction was not inhibited, but rather increased in mitotic cells, consistent with active translation initiation during mitosis. Phospho-defective substitution of 4E-BP1 at Ser-83 did not change global translation or individual mRNA translation profiles as measured by single-cell nascent protein synthesis and eIF4G RNA-immunoprecipitation sequencing. Mitotic 5’-terminal oligopyrimidine RNA translation was active and, unlike interphase translation, resistant to mTOR inhibition. Our findings reveal the phosphorylation profiles of 4E-BP1 isoforms and their interactions with eIF4E throughout the cell cycle and indicate that 4E-BP1 does not specifically inhibit translation initiation during mitosis.

2019-06-14 | GSE131668 | GEO

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

The eukaryotic translation initiation factor eIF4E elevates steady-state m7G capping of coding and noncoding transcripts

Project description:Methyl-7-guanosine (m7G) “capping” of coding and some noncoding RNAs is critical for their maturation and subsequent activity. Here, we discovered that eukaryotic translation initiation factor 4E(eIF4E), itself a cap-binding protein, drives the expression of the capping machinery and the increased capping efficiency of ∼100 coding and noncoding RNAs. This dataset collects transcriptomic data for quantitative cap immunoprecipitation (CapIP) assay in eIF4E-Flag or vector stable U2Os cells.

2020-09-30 | GSE158728 | GEO

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

Mus musculus

Project description:eIF4E phosphorylation promotes tumorigenesis and is associated with prostate cancer progression

| PRJNA118901 | ENA

Characterization of human malaria parasite Plasmodium falciparum eIF4E homologue and mRNA 5â² cap status

Project description:The mRNA 5â² cap is normally essential for eukaryotic mRNA translation, stabilization and transport and both the cap and eIF4E are important elements of post-transcriptional gene regulation. To further our understanding of mRNA translation in the human malaria parasite Plasmodium falciparum, we have investigated the parasite translation initiation factor eIF4E and its interaction with 5â² capped mRNA. We have purified P. falciparum eIF4E as a recombinant protein and demonstrated that it has canonical mRNA 5â² cap binding activity. We used this protein to purify P. falciparum full-length 5â² capped mRNAs from total parasite RNA. Microarray analysis comparing total and eIF4E-purified 5â² capped mRNAs shows that a subset of 34 features were more than two-fold under-represented in the purified RNA sample, including 19 features representative of nuclear transcripts. The uncapped nuclear transcripts may represent a class of mRNAs targeted for storage and cap removal. Keywords: total RNA vs purified capped mRNA The microarray data were obtained from four hybridizations using RNA from two independent GST-PfeIF4E purifications from separate malaria cultures.

2010-06-10 | E-GEOD-6356 | biostudies-arrayexpress

Characterization of human malaria parasite Plasmodium falciparum eIF4E homologue and mRNA 5′ cap status

Project description:The mRNA 5′ cap is normally essential for eukaryotic mRNA translation, stabilization and transport and both the cap and eIF4E are important elements of post-transcriptional gene regulation. To further our understanding of mRNA translation in the human malaria parasite Plasmodium falciparum, we have investigated the parasite translation initiation factor eIF4E and its interaction with 5′ capped mRNA. We have purified P. falciparum eIF4E as a recombinant protein and demonstrated that it has canonical mRNA 5′ cap binding activity. We used this protein to purify P. falciparum full-length 5′ capped mRNAs from total parasite RNA. Microarray analysis comparing total and eIF4E-purified 5′ capped mRNAs shows that a subset of 34 features were more than two-fold under-represented in the purified RNA sample, including 19 features representative of nuclear transcripts. The uncapped nuclear transcripts may represent a class of mRNAs targeted for storage and cap removal. Keywords: total RNA vs purified capped mRNA

2007-07-07 | GSE6356 | GEO

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