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EIF4GI Links Nutrient Sensing by mTOR to Cell Proliferation and Inhibition of Autophagy

ABSTRACT: Translation initiation factors have complex functions in cells which are not yet understood. We show that depletion of initiation factor eIF4GI only modestly reduces overall protein synthesis in cells, but phenocopies nutrient-starvation or inhibition of protein kinase mTOR, a key nutrient sensor. eIF4GI depletion impairs cell proliferation, bioenergetics and mitochondrial activity, thereby promoting autophagy. Translation of mRNAs involved in cell growth, proliferation and bioenergetics were selectively inhibited by reduction of eIF4GI, whereas mRNAs encoding proliferation inhibitors and catabolic pathway factors were increased. Depletion or over-expression of other eIF4G family members did not recapitulate these results. The majority of mRNAs that were translationally impaired with eIF4GI depletion were excluded from polyribosomes due to the presence of multiple upstream open reading frames and low mRNA abundance. These results suggest that the high levels of eIF4GI observed in many breast cancers might act to specifically increase proliferation, prevent autophagy and release tumor cells from control by nutrient sensing. Global regulation of transcription and polysomal association in eIF4GI-silenced cells. Keywords: Gene Silencing

ORGANISM(S): Homo sapiens

PROVIDER: GSE11011 | GEO | 2008/04/01

SECONDARY ACCESSION(S): PRJNA107097

REPOSITORIES: GEO

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siRNA of human MCF10A eIF4GI depleted cells vs. controls links nutrient sensing by mTOR to cell proliferation and inhibition of autophagy

Project description:Translation initiation factors have complex functions in cells which are not yet understood. We show that depletion of initiation factor eIF4GI only modestly reduces overall protein synthesis in cells, but phenocopies nutrient-starvation or inhibition of protein kinase mTOR, a key nutrient sensor. eIF4GI depletion impairs cell proliferation, bioenergetics and mitochondrial activity, thereby promoting autophagy. Translation of mRNAs involved in cell growth, proliferation and bioenergetics were selectively inhibited by reduction of eIF4GI, whereas mRNAs encoding proliferation inhibitors and catabolic pathway factors were increased. Depletion or over-expression of other eIF4G family members did not recapitulate these results. The majority of mRNAs that were translationally impaired with eIF4GI depletion were excluded from polyribosomes due to the presence of multiple upstream open reading frames and low mRNA abundance. These results suggest that the high levels of eIF4GI observed in many breast cancers might act to specifically increase proliferation, prevent autophagy and release tumor cells from control by nutrient sensing. Global regulation of transcription and polysomal association in eIF4GI-silenced cells. Experiment Overall Design: Two sets of experiments are presented. First, overall transcriptome changes were determined for control or eIF4GI silenced cells. Next, mRNAs associated with polysomes were compared between control and eIF4GI silenced cells.

2008-06-11 | E-GEOD-11011 | biostudies-arrayexpress

Transcriptional and translational effect of the lack of translation initiation factor eIF(iso)4E

2013-07-26 | GSE29386 | GEO

Transcriptional and translational effect of the lack of translation initiation factor eIF(iso)4E

Project description:One of the most regulated steps of translation initiation is the recruitment of an mRNA by the translation machinery. In eukaryotes, this step is mediated by the 5M-BM-4end cap-binding factor eIF4E bound to the bridge protein eIF4G and forming the eIF4F complex. In plants, different isoforms of eIF4E and eIF4G form the antigenically distinct eIF4F and eIF(iso)4F complexes proposed to mediate selective translation. Using a microarray analysis of polyribosome- and non-polyribosome-purified mRNAs from 15 day-old Arabidopsis thaliana wild type [WT] and eIF(iso)4E knockout mutant [AteIF(iso)4E-1] seedlings we found 79 transcripts shifted from polyribosomes toward non-polyribosomes, and 47 mRNAs with the opposite behavior in the mutant. The translationally decreased mRNAs were overrepresented in root-preferentially expressed genes and proteins from the endomembrane system, including several transporters such as the phosphate transporter PHOSPHATE1 (PHO1), Sucrose transporter 3 (SUC3), the ABC transporter-like with ATPase activity (MRP11) and five electron transporters, as well as signal transduction-, protein modification- and transcription-related proteins. For transcriptional analysis used total RNA of AteIF(iso)4E-1 seedlings of 15 days old to known the changes on transcripts leves by the eIF(iso)4E absence, using as control Wt seedlings. The experiments were performed in duplicate, and swap analysis were done. For translational analysis, used non-polysomal and polysomal RNA of AteIF(iso)4E-1 seedlings of 15 days old in order to known the transcripts that are modified in their translational levels by the eIF(iso)4E absence, using as control non polysomal and polysomal RNA of Wt seddlings.

2013-07-26 | E-GEOD-29386 | biostudies-arrayexpress

METTL3 promotes translation in human cancer cells

Project description:we find METTL3 associates with polyribosomes and promotes translation. METTL3 depletion inhibits translation, and both wild-type and catalytically inactive METTL3 promote translation when tethered to the 3' untranslated region (UTR) of a reporter mRNA. Mechanistically, METTL3 enhances mRNA translation through an interaction with the translation initiation machinery. m6A seq in A549 and H1299 cells, RNA seq in METTL3 knockdown cells

2016-07-03 | E-GEOD-76367 | biostudies-arrayexpress

Yeast eIF4G homogenic whole cell oxidative stress LC-MSMS

Project description:Translation initiation factor 4G (eIF4G) is an integral component of the eIF4F complex which is key to translation initiation for most eukaryotic mRNAs. Many eIF4G isoforms have been described in diverse eukaryotic organisms but we currently have a poor understanding of their functional roles and whether they regulate translation in an mRNA specific manner. The yeast Saccharomyces cerevisiae expresses two eIF4G isoforms, eIF4G1 and eIF4G2, that have previously been considered as functionally redundant with any phenotypic differences arising due to alteration in eIF4G expression levels. Using homogenic strains that express eIF4G1 or eIF4G2 as the sole eIF4G isoforms at comparable expression levels to total eIF4G, we show that eIF4G1 is specifically required to mediate the translational response to oxidative stress. We use quantitative proteomics to show that eIF4G1 promotes oxidative stress-specific proteome changes.

2023-10-24 | PXD041682 | Pride

METTL3 promotes translation in human cancer cells

2016-01-01 | GSE76367 | GEO

The ribosomal protein Asc1/RACK1 is required for efficient translation of short mRNAs

Project description:Translation is a core cellular process carried out by a highly conserved macromolecular machine, the ribosome. There has been remarkable evolutionary adaptation of this machine through the addition of eukaryote-specific ribosomal proteins whose individual effects on ribosome function are largely unknown. Here we show that eukaryote-specific Asc1/RACK1 is required for efficient translation of mRNAs with short open reading frames that show greater than average translational efficiency in diverse eukaryotes. ASC1 mutants in S. cerevisiae display compromised translation of specific functional groups, including cytoplasmic and mitochondrial ribosomal proteins, and display cellular phenotypes consistent with their gene-specific translation defects. Asc1-sensitive mRNAs are preferentially associated with the translational ‘closed loop’ complex comprised of eIF4E, eIF4G and Pab1, and depletion of eIF4G mimics the translational defects of ASC1 mutants. Together our results reveal a role for Asc1/RACK1 in a length-dependent initiation mechanism optimized for efficient translation of genes with important housekeeping functions.

2016-04-24 | GSE61753 | GEO

Translation initiation factor eIF4G1 preferentially binds yeast transcript leaders containing conserved oligo-uridine motifs

Project description:Translational control of gene expression plays essential roles in cellular stress responses and organismal development by enabling rapid, selective, and localized control of protein production. Translational regulation depends on context-dependent differences in the protein output of mRNAs, but the key mRNA features that distinguish efficiently translated mRNAs are largely unknown. Here we comprehensively determined the RNA-binding preferences of the initiation factor eIF4G to assess whether this core translation initiation factor has intrinsic sequence preferences that contribute to preferential translation of specific mRNAs.

2017-05-29 | GSE87614 | GEO

CERES is an eIF4E-interacting protein that forms non-canonical translation initiation complexes and modulates translation during the diel cycle in plants

Project description:Translation is a fundamental step in gene expression that regulates multiple developmental and stress responses. One key step of translation is the association between eIF4E and eIF4G. This process is regulated in different eukaryotes by proteins which bind to eIF4E and block the formation of the eIF4E/eIF4G complex. Here, we report the discovery of CERES, the first functional eIF4E regulator described in plants. CERES is a modular protein that contains a LRR domain and a canonical eIF4E binding site (4E-BS), critical for CERES interaction with eIF4E in planta. CERES/eIF4E interaction excludes eIF4G from the complex. Despite this observation, CERES promotes translation in vivo interacts with eIF4A and with eIF3 in vivo and cosediments with translation initiation complexes in sucrose gradients. Moreover, ceres mutants display a sharp increase of the 80S peak and a reduction of polysome content at specific periods of the diel cycle. Super-resolution ribosome profiling demonstrates that these mutants show a change of translation efficiency of mRNAs related to light response and glucose management. Consistently, these mutants show a hypersensitive response to glucose. These data show that CERES is a “non canonical” translation initiation factor that, through the formation of alternative translation initiation complexes, modulates translation during the light cycle in plants.

2019-12-04 | GSE124290 | GEO

Effect of stress on the binding affinity of yeast eIF4F components to their target RNAs

Project description:Translation factors eIF4E and eIF4G form eIF4F, which binds to mRNAs to promote ribosome recruitment and translation initiation. We were interested in analysing the effects of stresses on eIF4F interactions with individual mRNAs. We used a RIP-seq approach to assess how mRNA associations with eIF4E, eIF4G1 and eIF4G2 change in response to three stresses: 1) addition of hydrogen peroxide; 2) amino acids withdrawal; and, 3) glucose withdrawal. We find that acute stress leads to changes in eIF4FmRNA interactions that are shared among each factor and across the stresses imposed.

2017-10-11 | E-MTAB-5836 | biostudies-arrayexpress

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