Similar Datasets
Project description:Protein synthesis is metabolically costly, and the level of translation must match nutrient availability and cellular needs. Overall protein synthesis levels are modulated by regulating translation initiation. The cap-binding protein eIF4E—the earliest contact between mRNAs and the translation machinery—serves as one point of control, but its contributions to mRNA-specific translation regulation remain poorly understood. We acutely depleted eIF4E, which is essential in budding yeast, and observed surprisingly modest effects on cell growth and protein synthesis. Long-lived transcripts were downregulated, likely reflecting accelerated turnover, and the strongest gene-specific effects arose as secondary effects of reduced protein biosynthesis on amino acid pools. Futile cycles of amino acid synthesis and degradation were accompanied by translational activation of GCN4, which is typically induced by amino acid starvation. We further identified translational tuning of PCL5, a negative regulator of Gcn4, that provides a consistent protein-to-mRNA ratio under varying translation environments. This translational control depended in part on a uniquely long poly-(A) tract in the PCL5 5’ UTR and on poly-(A) binding protein. These results highlight the intricate interplay between translation, amino acid homeostasis, and gene regulation and uncover new layers of feedback control in cellular response to stress and nutrient availability.
2023-05-09 | GSE231757 | GEO
Project description:Protein synthesis is metabolically costly, and the level of translation must match nutrient availability and cellular needs. Overall protein synthesis levels are modulated by regulating translation initiation. The cap-binding protein eIF4E—the earliest contact between mRNAs and the translation machinery—serves as one point of control, but its contributions to mRNA-specific translation regulation remain poorly understood. We acutely depleted eIF4E, which is essential in budding yeast, and observed surprisingly modest effects on cell growth and protein synthesis. Long-lived transcripts were downregulated, likely reflecting accelerated turnover, and the strongest gene-specific effects arose as secondary effects of reduced protein biosynthesis on amino acid pools. Futile cycles of amino acid synthesis and degradation were accompanied by translational activation of GCN4, which is typically induced by amino acid starvation. We further identified translational tuning of PCL5, a negative regulator of Gcn4, that provides a consistent protein-to-mRNA ratio under varying translation environments. This translational control depended in part on a uniquely long poly-(A) tract in the PCL5 5’ UTR and on poly-(A) binding protein. These results highlight the intricate interplay between translation, amino acid homeostasis, and gene regulation and uncover new layers of feedback control in cellular response to stress and nutrient availability.
2023-05-09 | GSE231756 | GEO
Project description:Protein synthesis is metabolically costly, and the level of translation must match nutrient availability and cellular needs. Overall protein synthesis levels are modulated by regulating translation initiation. The cap-binding protein eIF4E—the earliest contact between mRNAs and the translation machinery—serves as one point of control, but its contributions to mRNA-specific translation regulation remain poorly understood. We acutely depleted eIF4E, which is essential in budding yeast, and observed surprisingly modest effects on cell growth and protein synthesis. Long-lived transcripts were downregulated, likely reflecting accelerated turnover, and the strongest gene-specific effects arose as secondary effects of reduced protein biosynthesis on amino acid pools. Futile cycles of amino acid synthesis and degradation were accompanied by translational activation of GCN4, which is typically induced by amino acid starvation. We further identified translational tuning of PCL5, a negative regulator of Gcn4, that provides a consistent protein-to-mRNA ratio under varying translation environments. This translational control depended in part on a uniquely long poly-(A) tract in the PCL5 5’ UTR and on poly-(A) binding protein. These results highlight the intricate interplay between translation, amino acid homeostasis, and gene regulation and uncover new layers of feedback control in cellular response to stress and nutrient availability.
2023-05-09 | GSE231758 | GEO
Project description:Dysregulation of amino acid metabolism upon rapid depletion of cap-binding protein eIF4E
| PRJNA967635 | ENA
Project description:Dysregulation of amino acid metabolism upon rapid depletion of cap-binding protein eIF4E [pcl5_screen]
| PRJNA967638 | ENA
Project description:Dysregulation of amino acid metabolism upon rapid depletion of cap-binding protein eIF4E [aro10_screen]
| PRJNA967637 | ENA
Project description:Dysregulation of amino acid metabolism upon rapid depletion of cap-binding protein eIF4E [RNA-Seq]
| PRJNA967640 | ENA
Project description:Translational control of gene expression plays a key role in many biological processes. Consequently, the activity of the translation apparatus is under tight homeostatic control. eIF4E, the mRNA 5' cap-binding protein, facilitates cap-dependent translation and is a major target for translational control. eIF4E activity is controlled by a family of repressor proteins, termed 4E-binding proteins (4E-BPs). Here, we describe the surprising finding that despite the importance of eIF4E for translation, a drastic knockdown of eIF4E caused only minor reduction in translation. This conundrum can be explained by the finding that 4E-BP1 is degraded in eIF4E-knockdown cells. Hypophosphorylated 4E-BP1, which binds to eIF4E, is degraded, whereas hyperphosphorylated 4E-BP1 is refractory to degradation. We identified the KLHL25-CUL3 complex as the E3 ubiquitin ligase, which targets hypophosphorylated 4E-BP1. Thus, the activity of eIF4E is under homeostatic control via the regulation of the levels of its repressor protein 4E-BP1 through ubiquitination.
| S-EPMC4085128 | biostudies-literature
Project description:All eukaryotic mRNAs possess a 5'-cap (m(7)GpppN) that is recognized by a family of cap-binding proteins. These participate in various processes, such as RNA transport and stabilization, as well as in assembly of the translation initiation complex. The 5'-cap of trypanosomatids is complex; in addition to 7-methyl guanosine, it includes unique modifications on the first four transcribed nucleotides, and is thus denoted cap-4. Here we analyze a cap-binding protein of Leishmania, in an attempt to understand the structural features that promote its binding to this unusual cap. LeishIF4E-1, a homolog of eIF4E, contains the conserved cap-binding pocket, similar to its mouse counterpart. The mouse eIF4E has a higher K(as) for all cap analogs tested, as compared with LeishIF4E-1. However, whereas the mouse eIF4E shows a fivefold higher affinity for m(7)GTP than for a chemically synthesized cap-4 structure, LeishIF4E-1 shows similar affinities for both ligands. A sequence alignment shows that LeishIF4E-1 lacks the region that parallels the C terminus in the murine eIF4E. Truncation of this region in the mouse protein reduces the difference that is observed between its binding to m(7)GTP and cap-4, prior to this deletion. We hypothesize that variations in the structure of LeishIF4E-1, possibly also the absence of a region that is homologous to the C terminus of the mouse protein, promote its ability to interact with the cap-4 structure. LeishIF4E-1 is distributed in the cytoplasm, but its function is not clear yet, because it cannot substitute the mammalian eIF4E in a rabbit reticulocyte in vitro translation system.
| S-EPMC1370664 | biostudies-literature
Project description:Dysregulated protein synthesis is frequently involved in oncogenesis and cancer progression. Translation initiation is thought to be the rate-limiting step in protein synthesis, and the mRNA 5' cap-binding protein eukaryotic translation initiation factor 4E (eIF4E) is a pivotal factor that initiates translation. The activities of eIF4E are regulated at multiple levels, one of which is through its phosphorylation at Serine 209 by the mitogen-activated protein kinase-interacting kinases (MNKs, including MNK1 and MNK2). Benefiting from novel mouse genetic tools and pharmacological MNK inhibitors, our understanding of a role for eIF4E phosphorylation in tumor biology and cancer therapy has greatly evolved in recent years. Importantly, recent studies have found that the level of eIF4E phosphorylation is frequently upregulated in a wide variety of human cancer types, and phosphorylation of eIF4E drives a number of important processes in cancer biology, including cell transformation, proliferation, apoptosis, metastasis and angiogenesis. The MNK-eIF4E axis is being assessed as a therapeutic target either alone or in combination with other therapies in different cancer models. As novel MNK inhibitors are being developed, experimental studies bring new hope to cure human cancers that are not responsive to traditional therapies. Herein we review recent progress on our understanding of a mechanistic role for phosphorylation of eIF4E in cancer biology and therapy.
| S-EPMC8049097 | biostudies-literature