Overexpression of eukaryotic translation initiation factor, eIF4E confers tamoxifen resistance in breast cancer via the ERα/FOXM1 axis
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE132851 | GEO | 2019/06/18
REPOSITORIES: GEO
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Project description:Overexpression of eukaryotic translation initiation factor, eIF4E confers tamoxifen resistance in breast cancer via the ERα/FOXM1 axis
| PRJNA549272 | ENA
Project description:Recent advances in understanding the role of eukaryotic translation initiator factor 4E (eIF4E) in tumorigenesis and cancer progression have generated significant interest in therapeutic agents that indirectly or directly target aberrant activation of eIF4E in cancer. Here, we address the general function of eIF4E in translation initiation and cancer, present evidence supporting its role in cancer initiation and progression, and highlight emerging therapeutics that efficiently target hyperactivated eIF4E. In doing so, we also highlight the major differences between these therapeutics that may influence their mechanism of action.
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Project description:Aberrant splicing is typically attributed to splice-factor (SF) mutation and contributes to malignancies including acute myeloid leukemia (AML). Here, we discovered a mutation-independent means to extensively reprogram alternative splicing (AS). We showed that the dysregulated expression of eukaryotic translation initiation factor eIF4E elevated selective splice-factor production, thereby impacting multiple spliceosome complexes, including factors mutated in AML such as SF3B1 and U2AF1. These changes generated a splicing landscape that predominantly supported altered splice-site selection for ~800 transcripts in cell lines and ~4,600 transcripts in specimens from high-eIF4E AML patients otherwise harboring no known SF mutations. Nuclear RNA immunoprecipitations, export assays, polysome analyses, and mutational studies together revealed that eIF4E primarily increased SF production via its nuclear RNA export activity. By contrast, eIF4E dysregulation did not induce known SF mutations or alter spliceosome number. eIF4E interacted with the spliceosome and some pre-mRNAs, suggesting its direct involvement in specific splicing events. eIF4E induced simultaneous effects on numerous SF proteins, resulting in a much larger range of splicing alterations than in the case of mutation or dysregulation of individual SFs and providing a novel paradigm for splicing control and dysregulation.
| S-EPMC10068332 | biostudies-literature
Project description:Aberrant splicing is typically attributed to splice-factor (SF) mutation and contributes to malignancies including acute myeloid leukemia (AML). Here, we discovered a mutation-independent means to extensively reprogramme alternative splicing (AS). We showed that dysregulated expression of eukaryotic translation initiation factor eIF4E elevated selective splice factor production, thereby impacting multiple spliceosome complexes, including factors mutated in AML such as SF3B1 and U2AF1. These changes generated a splicing landscape that predominantly supported altered splice-site selection for ~800 transcripts in cell lines and ~4600 transcripts in specimens from high-eIF4E AML patients otherwise harbouring no known SF mutations. Nuclear RNA immunoprecipitations, export assays, polysome analyses and mutational studies together revealed that eIF4E primarily increased SF production via its nuclear RNA export activity. In contrast, eIF4E dysregulation did not induce known SF mutations or alter spliceosome number. eIF4E interacted with the spliceosome and some pre-mRNAs, suggesting its direct involvement in specific splicing events. eIF4E induced simultaneous effects on numerous SF proteins, resulting in a much larger range of splicing alterations than in than case of mutation or dysregulation of individual SFs and providing a novel paradigm for splicing control and dysregulation.
| S-SCDT-10_15252-EMBJ_2021110496 | biostudies-other
Project description:The eukaryotic translation initiation factor eIF4E plays important roles in controlling the composition of the proteome. Indeed, dysregulation of eIF4E is associated with poor prognosis cancers. The traditional view has been that eIF4E acts solely in translation. However, over the last ?25 years, eIF4E was found in the nucleus where it acts in mRNA export and in the last ?10 years, eIF4E was found in cytoplasmic processing bodies (P-bodies) where it functions in mRNA sequestration and stability. The common biochemical thread for these activities is the ability of eIF4E to bind the 7-methylguanosine cap on the 5' end of mRNAs. Recently, the possibility that eIF4E directly binds some mRNA elements independently of the cap has also been raised. Importantly, the effects of eIF4E are not genome-wide with a subset of transcripts targeted depending on the presence of specific mRNA elements and context-dependent regulatory factors. Indeed, eIF4E governs RNA regulons through co-regulating the expression of groups of transcripts acting in the same biochemical pathways. In addition, studies over the past ?15 years indicate that there are multiple strategies that regulatory factors employ to modulate eIF4E activities in context-dependent manners. This perspective focuses on these new findings and incorporates them into a broader model for eIF4E function.
| S-EPMC5173310 | biostudies-literature
Project description:The PI3K pathway is frequently activated in cancer; therefore, considerable effort is focused on identifying compounds that can inhibit specific pathway components, particularly the hallmark oncogene PIK3CA. Although targeted inhibition of a cancer survival gene holds significant promise, there are concerns that drug resistance may emerge within the cancerous cells, thus limiting clinical efficacy. Using genetically defined human mammary epithelial cells, we evolved resistance to the PI3K/mammalian target of rapamycin (mTOR) inhibitor BEZ235, and by genome-wide copy number analyses, we identified MYC and eIF4E amplification within the resistant cells. Importantly, either MYC or eukaryotic translation initiation factor 4E (eIF4E) was required to bypass pharmacological PI3K/mTOR inhibition in resistant cells. Furthermore, these cells displayed elevated 5' cap-dependent protein translation. Collectively, these findings suggest that analysis of drivers of protein translation could facilitate the identification of cancer lesions that confer resistance to PI3K pathway-targeted drugs.
| S-EPMC3174675 | biostudies-literature
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. Phosphorylation 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 investigated 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 electrophoretic 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. Phosphodefective 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.
| S-EPMC6682726 | biostudies-literature
Project description:This SuperSeries is composed of the following subset Series: GSE25170: MYC drives resistance to PI3K/mTOR targeted inhibition (Sty SNP array) GSE25172: MYC drives resistance to PI3K/mTOR targeted inhibition (gene expression) Refer to individual Series
2011-09-13 | E-GEOD-25173 | biostudies-arrayexpress
Project description:The eukaryotic translation initiation factor eIF4E is a potent oncogene. Although eIF4E has traditional roles in translation initiation in the cytoplasm, it is also found in the nucleus, suggesting that it has activities beyond its role in protein synthesis. The road less traveled has been taken to study these nuclear activities and to understand their contribution to the oncogenic potential of eIF4E. The molecular features and biological pathways underpinning eIF4E's nuclear mRNA export are described. New classes of eIF4E regulators have been identified and their relevance to cancer shown. The studies presented here reveal the molecular, biophysical, and structural bases for eIF4E regulation. Finally, recent clinical work targeting eIF4E in acute myeloid leukemia patients with ribavirin is discussed. In summary, these findings provide a novel paradigm for eIF4E function and the molecular basis for targeting it in leukemia patients.
| S-EPMC4269245 | biostudies-literature
Project description:The microenvironment provides a functional substratum supporting tumour growth. Hyaluronan (HA) is a major component of this structure. While the role of HA in malignancy is well-defined, the mechanisms driving its biosynthesis in cancer are poorly understood. We show that the eukaryotic translation initiation factor eIF4E, an oncoprotein, drives HA biosynthesis. eIF4E stimulates production of enzymes that synthesize the building blocks of HA, UDP-Glucuronic acid and UDP-N-Acetyl-Glucosamine, as well as hyaluronic acid synthase which forms the disaccharide chain. Strikingly, eIF4E inhibition alone repressed HA levels as effectively as directly targeting HA with hyaluronidase. Unusually, HA was retained on the surface of high-eIF4E cells, rather than being extruded into the extracellular space. Surface-associated HA was required for eIF4E's oncogenic activities suggesting that eIF4E potentiates an oncogenic HA program. These studies provide unique insights into the mechanisms driving HA production and demonstrate that an oncoprotein can co-opt HA biosynthesis to drive malignancy.
| S-EPMC5705209 | biostudies-literature