Homo sapiens
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA261845 | ENA |
REPOSITORIES: ENA
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Project description:The phosphorylation of eIF4E1 at serine 209 by MNK1 or MNK2 has been shown to initiate oncogenic mRNA translation, a process that favours cancer development and maintenance. Here, we interrogate the MNK-eIF4E axis in diffuse large B-cell lymphoma (DLBCL) and show a distinct distribution of MNK1 and MNK2 in germinal centre B-cell (GCB) and activated B-cell (ABC) DLBCL. Despite displaying a differential distribution in GCB and ABC, both MNKs functionally complement each other to sustain cell survival. MNK inhibition ablates eIF4E1 phosphorylation and concurrently enhances eIF4E3 expression. Loss of MNK protein itself down-regulates total eIF4E1 protein level by reducing eIF4E1 mRNA polysomal loading without affecting total mRNA level or stability. Enhanced eIF4E3 expression marginally suppresses eIF4E1-driven translation but exhibits a unique translatome that unveils a novel role for eIF4E3 in translation initiation. Together, we propose that MNKs can modulate oncogenic translation by regulating eIF4E1-eIF4E3 levels and activity in DLBCL.
2014-11-18 | GSE61691 | GEO
Project description:The phosphorylation of eIF4E1 at serine 209 by MNK1 or MNK2 has been shown to initiate oncogenic mRNA translation, a process that favours cancer development and maintenance. Here, we interrogate the MNK-eIF4E axis in diffuse large B-cell lymphoma (DLBCL) and show a distinct distribution of MNK1 and MNK2 in germinal centre B-cell (GCB) and activated B-cell (ABC) DLBCL. Despite displaying a differential distribution in GCB and ABC, both MNKs functionally complement each other to sustain cell survival. MNK inhibition ablates eIF4E1 phosphorylation and concurrently enhances eIF4E3 expression. Loss of MNK protein itself down-regulates total eIF4E1 protein level by reducing eIF4E1 mRNA polysomal loading without affecting total mRNA level or stability. Enhanced eIF4E3 expression marginally suppresses eIF4E1-driven translation but exhibits a unique translatome that unveils a novel role for eIF4E3 in translation initiation. Together, we propose that MNKs can modulate oncogenic translation by regulating eIF4E1-eIF4E3 levels and activity in DLBCL. As the knockdown of eIF4E1 or eIF4E3 caused significant cell death, we overexpressed either protein in HLY-1 cells and performed sucrose density gradient fractionation. RNA was extracted from polysome fractions #9-10, containing highly translated polysome-bound mRNAs, from total RNA and from an empty vector control. These samples, in triplicate, were used for either translatome or transcriptome analysis using Illumina HumanHT-12 v4 BeadChips for gene expression analysis.
2014-11-18 | E-GEOD-61691 | biostudies-arrayexpress
Project description:Ingestion of Toxoplasma gondii results in life-long infection due to its ability to convert from the rapidly disseminating tachyzoite stage to the chronic, encysted bradyzoite stage. The control of mRNA translation has been suggested to play a key role in the signaling required to trigger bradyzoite formation. In eukaryotes, translational control primarily operates at two key points during the assembly of translation initiation factors. The phosphorylation of eIF2 affects mRNA start codon recognition and promotes differentiation in a variety of parasites. Modulating eIF4F function is the second pan-eukaryote regulatory point but remains unexplored in Toxoplasma. Here, we uncover the role that eIF4F-centric regulation plays in regulating bradyzoite formation by targeting the cap-binding subunit, eIF4E1. We discover that eIF4E1 coordinates two eIF4F complexes and binds the 5’-end of all mRNAs transcribed in tachyzoites, many of which show evidence of stemming from heterogenous transcriptional start sites. Together, this indicates that eIF4E1 is the predominant cap-binding protein in Toxoplasma tachyzoites. We also demonstrate that eIF4E1 knockdown or its chemical inhibition triggers the efficient formation of bradyzoites in the absence of other stresses and that stress-induced bradyzoites reduce their eIF4E1 expression. This study unearths a role for eIF4F-centric translational control in controlling Toxoplasma differentiation, suggesting that control of cap-dependent translation regulates the process of bradyzoite formation.
2023-11-02 | GSE243206 | GEO
Project description:Ingestion of Toxoplasma gondii results in life-long infection due to its ability to convert from the rapidly disseminating tachyzoite stage to the chronic, encysted bradyzoite stage. The control of mRNA translation has been suggested to play a key role in the signaling required to trigger bradyzoite formation. In eukaryotes, translational control primarily operates at two key points during the assembly of translation initiation factors. The phosphorylation of eIF2 affects mRNA start codon recognition and promotes differentiation in a variety of parasites. Modulating eIF4F function is the second pan-eukaryote regulatory point but remains unexplored in Toxoplasma. Here, we uncover the role that eIF4F-centric regulation plays in regulating bradyzoite formation by targeting the cap-binding subunit, eIF4E1. We discover that eIF4E1 coordinates two eIF4F complexes and binds the 5’-end of all mRNAs transcribed in tachyzoites, many of which show evidence of stemming from heterogenous transcriptional start sites. Together, this indicates that eIF4E1 is the predominant cap-binding protein in Toxoplasma tachyzoites. We also demonstrate that eIF4E1 knockdown or its chemical inhibition triggers the efficient formation of bradyzoites in the absence of other stresses and that stress-induced bradyzoites reduce their eIF4E1 expression. This study unearths a role for eIF4F-centric translational control in controlling Toxoplasma differentiation, suggesting that control of cap-dependent translation regulates the process of bradyzoite formation.
2023-11-02 | GSE243203 | GEO
Project description:The unicellular eukaryote Trypanosoma brucei relies heavily on posttranscriptional regulatory mechanisms, as pol II transcription is polycistronic. The parasite has six isoforms of the cap-binding translation initiation factor eIF4E, and five eiF4Gs (PMID: 29077018), which potentially allow for differential mRNA target selection in order to fine-tune translation. EIF4E3 and EIF4E4 appear to be general initiation factors; we are investigating the EIF4E proteins that are presumed to have more specialized functions, i.e., EIF4E1, EIF4E2, EIF4E5, and EIF4E6. EIF4E1 interacts with 4E-interacting protein (4EIP) and not with any EIF4G; they functionally resemble mammalian 4E-HP and GIGYF2. 4EIP suppresses translation and provokes mRNA degradation. 4EIP and EIF4E1 are dispensable in slender “bloodstream forms” (BSFs), which multiply in mammals, but 4EIP is required for translation suppression in the growth-arrested “stumpy” BSF (PMID: 30124912). Meanwhile EIF4E1, but not 4EIP, is required for survival of “procyclic forms” (PCFs), which grow in Tsetse. Tethered EIF4E1 is suppressive only when 4EIP is present. We are investigating whether it can, without an EIF4G, activate translation in BSFs/PCFs, as well as how target mRNAs are selected in absence and presence of 4EIP, based on the proteins it associates with. Like EIF4E1, EIF4E2 does not interact with any EIF4G protein, but was found in association with a homolog of the histone mRNA stem-loop-binding protein, called SLBP2, in PCFs (PMID: 29288414). The protein binding partners in BSFs have not been addressed this far. EIF4E3, EIF4E4, EIF4E5, and EIF4E6 all stimulate expression when tethered. They interact with different EIF4G homologs, and each is essential in at least one life-cycle stage, indicating that each serves a distinct role. We have now evidence that EIF4E6 interacts specifically, not only with EIF4G5, but also with a previously characterized stimulatory complex containing MKT1, PBP1, and LSM12, which we aimed to confirm by this quantitative mass spectrometry approach. The complex is recruited to mRNAs via sequence-specific RNA-binding proteins (PMID: 24470144), offering a novel mechanism for specific translation activation by the EIF4E6-EIF4G5 complex. EIF4E5 on the other hand associates with either EIF4G1 or EIF4G2 to exert its functions. It is dispensable in the BSF, but essential in PCFs, where knock-down results in a motility-related phenotype. Furthermore, previous studies identified several 14-3-3 homologs to be associated with EIF4E5 in complex with either EIF4G1 or EIF4G2 in PCFs (PMID: 24962368). In the course of this study, PTP-tagged versions of EIF4E1+/- 4EIP (BSF, PCF), EIF4E2, EIF4E5, and EIF4E6 (BSF only) were pulled down and bound proteins were analyzed by quantitative mass spectrometry, with EIF4E3-PTP (BSF) and GFP-PTP (BSF, PCF) serving as controls.
2021-05-28 | PXD025913 | Pride
Project description:Kynureninase is a member of a large family of catalytically diverse but structurally homologous pyridoxal 5'-phosphate (PLP) dependent enzymes known as the aspartate aminotransferase superfamily or alpha-family. The Homo sapiens and other eukaryotic constitutive kynureninases preferentially catalyze the hydrolytic cleavage of 3-hydroxy-l-kynurenine to produce 3-hydroxyanthranilate and l-alanine, while l-kynurenine is the substrate of many prokaryotic inducible kynureninases. The human enzyme was cloned with an N-terminal hexahistidine tag, expressed, and purified from a bacterial expression system using Ni metal ion affinity chromatography. Kinetic characterization of the recombinant enzyme reveals classic Michaelis-Menten behavior, with a Km of 28.3 +/- 1.9 microM and a specific activity of 1.75 micromol min-1 mg-1 for 3-hydroxy-dl-kynurenine. Crystals of recombinant kynureninase that diffracted to 2.0 A were obtained, and the atomic structure of the PLP-bound holoenzyme was determined by molecular replacement using the Pseudomonas fluorescens kynureninase structure (PDB entry 1qz9) as the phasing model. A structural superposition with the P. fluorescens kynureninase revealed that these two structures resemble the "open" and "closed" conformations of aspartate aminotransferase. The comparison illustrates the dynamic nature of these proteins' small domains and reveals a role for Arg-434 similar to its role in other AAT alpha-family members. Docking of 3-hydroxy-l-kynurenine into the human kynureninase active site suggests that Asn-333 and His-102 are involved in substrate binding and molecular discrimination between inducible and constitutive kynureninase substrates.
| S-EPMC2531291 | biostudies-literature
Project description:RNA extracted at 240min. Samples are rRNA depleted. Expression measurement of Homo sapiens genes.
2019-07-31 | GSE114179 | GEO
Project description:A post-translational regulatory switch on UPF1 controls targeted mRNA degradation.
| PRJNA257379 | ENA
Project description:As the evolution of miRNA genes has been found to be one of the important factors in formation of the modern type of man, we performed a comparative analysis of the evolution of miRNA genes in two archaic hominines, Homo sapiens neanderthalensis and Homo sapiens denisova, and elucidated the expression of their target mRNAs in bain.A comparative analysis of the genomes of primates, including species in the genus Homo, identified a group of miRNA genes having fixed substitutions with important implications for the evolution of Homo sapiens neanderthalensis and Homo sapiens denisova. The mRNAs targeted by miRNAs with mutations specific for Homo sapiens denisova exhibited enhanced expression during postnatal brain development in modern humans. By contrast, the expression of mRNAs targeted by miRNAs bearing variations specific for Homo sapiens neanderthalensis was shown to be enhanced in prenatal brain development.Our results highlight the importance of changes in miRNA gene sequences in the course of Homo sapiens denisova and Homo sapiens neanderthalensis evolution. The genetic alterations of miRNAs regulating the spatiotemporal expression of multiple genes in the prenatal and postnatal brain may contribute to the progressive evolution of brain function, which is consistent with the observations of fine technical and typological properties of tools and decorative items reported from archaeological Denisovan sites. The data also suggest that differential spatial-temporal regulation of gene products promoted by the subspecies-specific mutations in the miRNA genes might have occurred in the brains of Homo sapiens denisova and Homo sapiens neanderthalensis, potentially contributing to the cultural differences between these two archaic hominines.
| S-EPMC4686780 | biostudies-literature
Project description:PurposeWe investigated the evidence of recent positive selection in the human phototransduction system at single nucleotide polymorphism (SNP) and gene level.MethodsSNP genotyping data from the International HapMap Project for European, Eastern Asian, and African populations was used to discover differences in haplotype length and allele frequency between these populations. Numeric selection metrics were computed for each SNP and aggregated into gene-level metrics to measure evidence of recent positive selection. The level of recent positive selection in phototransduction genes was evaluated and compared to a set of genes shown previously to be under recent selection, and a set of highly conserved genes as positive and negative controls, respectively.ResultsSix of 20 phototransduction genes evaluated had gene-level selection metrics above the 90th percentile: RGS9, GNB1, RHO, PDE6G, GNAT1, and SLC24A1. The selection signal across these genes was found to be of similar magnitude to the positive control genes and much greater than the negative control genes.ConclusionsThere is evidence for selective pressure in the genes involved in retinal phototransduction, and traces of this selective pressure can be demonstrated using SNP-level and gene-level metrics of allelic variation. We hypothesize that the selective pressure on these genes was related to their role in low light vision and retinal adaptation to ambient light changes. Uncovering the underlying genetics of evolutionary adaptations in phototransduction not only allows greater understanding of vision and visual diseases, but also the development of patient-specific diagnostic and intervention strategies.
| S-EPMC3743458 | biostudies-literature