scholarly journals The m6A reader YTHDF1 promotes ovarian cancer progression via augmenting EIF3C translation

2020 ◽  
Vol 48 (7) ◽  
pp. 3816-3831 ◽  
Author(s):  
Tao Liu ◽  
Qinglv Wei ◽  
Jing Jin ◽  
Qingya Luo ◽  
Yi Liu ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cancer Patients ◽  
Cancer Progression ◽  
Protein Translation ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Rna Modification ◽  
Dependent Manner ◽  
The Novel ◽  
A Subunit

Abstract N 6-Methyladenosine (m6A) is the most abundant RNA modification in mammal mRNAs and increasing evidence suggests the key roles of m6A in human tumorigenesis. However, whether m6A, especially its ‘reader’ YTHDF1, targets a gene involving in protein translation and thus affects overall protein production in cancer cells is largely unexplored. Here, using multi-omics analysis for ovarian cancer, we identified a novel mechanism involving EIF3C, a subunit of the protein translation initiation factor EIF3, as the direct target of the YTHDF1. YTHDF1 augments the translation of EIF3C in an m6A-dependent manner by binding to m6A-modified EIF3C mRNA and concomitantly promotes the overall translational output, thereby facilitating tumorigenesis and metastasis of ovarian cancer. YTHDF1 is frequently amplified in ovarian cancer and up-regulation of YTHDF1 is associated with the adverse prognosis of ovarian cancer patients. Furthermore, the protein but not the RNA abundance of EIF3C is increased in ovarian cancer and positively correlates with the protein expression of YTHDF1 in ovarian cancer patients, suggesting modification of EIF3C mRNA is more relevant to its role in cancer. Collectively, we identify the novel YTHDF1-EIF3C axis critical for ovarian cancer progression which can serve as a target to develop therapeutics for cancer treatment.

scholarly journals Inhibition of eEF2K synergizes with glutaminase inhibitors or 4EBP1 depletion to suppress growth of triple-negative breast cancer cells

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
YoungJun Ju ◽  
Yaacov Ben-David ◽  
Daniela Rotin ◽  
Eldad Zacksenhaus
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Translation Initiation ◽  
Triple Negative ◽  
Elongation Factor ◽  
Protein Translation ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Related Factors ◽  
Metabolic Conditions

AbstractThe eukaryotic elongation factor-2 kinase, eEF2K, which restricts protein translation elongation, has been identified as a potential therapeutic target for diverse types of malignancies including triple negative breast cancer (TNBC). However, the contexts in which eEF2K inhibition is essential in TNBC and its consequences on the proteome are largely unknown. Here we show that genetic or pharmacological inhibition of eEF2K cooperated with glutamine (Gln) starvation, and synergized with glutaminase (GLS1) inhibitors to suppress growth of diverse TNBC cell lines. eEF2K inhibition also synergized with depletion of eukaryotic translation initiation factor 4E-binding protein 1 (eIF4EBP1; 4EBP1), a suppressor of eukaryotic protein translation initiation factor 4E (eIF4E), to induce c-MYC and Cyclin D1 expression, yet attenuate growth of TNBC cells. Proteomic analysis revealed that whereas eEF2K depletion alone uniquely induced Cyclin Dependent Kinase 1 (CDK1) and 6 (CDK6), combined depletion of eEF2K and 4EBP1 resulted in overlapping effects on the proteome, with the highest impact on the ‘Collagen containing extracellular matrix’ pathway (e.g. COL1A1), as well as the amino-acid transporter, SLC7A5/LAT1, suggesting a regulatory loop via mTORC1. In addition, combined depletion of eEF2K and 4EBP1 indirectly reduced the levels of IFN-dependent innate immune response-related factors. Thus, eEF2K inhibition triggers cell cycle arrest/death under unfavourable metabolic conditions such as Gln-starvation/GLS1 inhibition or 4EBP1 depletion, uncovering new therapeutic avenues for TNBC and underscoring a pressing need for clinically relevant eEF2K inhibitors.

Update on Phytochemical and Biological Studies on Rocaglate Derivatives from Aglaia Species

Planta Medica ◽  
2021 ◽  
Author(s):  
Garima Agarwal ◽  
Long-Sheng Chang ◽  
Djaja Doel Soejarto ◽  
A. Douglas Kinghorn
Keyword(s):  
Biological Activities ◽  
Chemical Constituents ◽  
Protein Translation ◽  
Biological Properties ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Eukaryotic Translation ◽  
Ability To Act ◽  
Biological Studies ◽  
Phytochemical Constituents

AbstractWith about 120 species, Aglaia is one of the largest genera of the plant family Meliaceae (the mahogany plants). It is native to the tropical rainforests of the Indo-Australian region, ranging from India and Sri Lanka eastward to Polynesia and Micronesia. Various Aglaia species have been investigated since the 1960s for their phytochemical constituents and biological properties, with the cyclopenta[b]benzofurans (rocaglates or flavaglines) being of particular interest. Phytochemists, medicinal chemists, and biologists have conducted extensive research in establishing these secondary metabolites as potential lead compounds with antineoplastic and antiviral effects, among others. The varied biological properties of rocaglates can be attributed to their unusual structures and their ability to act as inhibitors of the eukaryotic translation initiation factor 4A (eIF4A), affecting protein translation. The present review provides an update on the recently reported phytochemical constituents of Aglaia species, focusing on rocaglate derivatives. Furthermore, laboratory work performed on investigating the biological activities of these chemical constituents is also covered.

Abstract 1394: Sublethal Levels of Aldehydes Augmented Cardiac Anti-Oxidant Defense through Activation of eIF2 α -ATF4 Pathway via GCN2 Kinase

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Takaharu Katayama ◽  
Motoaki Sano ◽  
Jin Endo ◽  
Kentaro Hayashida ◽  
Tomohiro Matsuhashi ◽  
...  
Keyword(s):  
Amino Acid ◽  
Amino Acid Metabolism ◽  
Acid Metabolism ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Special Importance ◽  
Dependent Manner ◽  
Protein Levels

[Introduction] Despite an increase in the levels of aldehydes, the heart from aldehyde dehydrogenase ( ALDH ) 2*2 -transgenic (Tg) mice, loss of function model of ALDH, exhibited a greater tolerance to oxidative stress via activation of amino acid metabolism leading to glutathione biosynthesis. This study was designed to identify the signaling cascades responsible for the activation of amino acid metabolism by aldehydes. [Methods & Results] (1) Phosphorylation of α -subunit of eukaryotic translation initiation factor 2 (eIF2 α ) and subsequent translational activation of ATF4 have been shown to induce amino acid metabolism as a common response to a wide variety of stressors. Consistent with this, phosphorylation levels of eIF2 α and protein expression of ATF4 were increased in ALDH2*2 -Tg hearts. (2) Among four eIF2 α kinases, general control non-depressible (GCN)2 kinase, a sensor for amino acid insufficiency, was activated in ALDH2*2 -Tg heart. (3) Quantification of intracellular amino acid demonstrated that free histidine concentration in ALDH2*2 -Tg heart was selectively reduced by 50% compared to that in non-Tg littermates. (4) To clarify the functional significance of observed reduction in histidine, ALDH2*2 -Tg mice were fed a high histidine diet. The phosphorylation levels of eIF2 α and the protein levels of ATF4 were diminished by 50% in ALDH2*2 -Tg mice fed the high histidine diet, in agreement with the normalization of histidine concentration. Accordingly, both enhanced tolerance to ischemia-reperfusion injury and elevated levels of glutathione were partially diminished in the heart from ALDH2*2 -Tg mice fed the high histidine diet compared to ALDH2*2 -Tg mice fed normal chow. (5) In culture, exposure to 4-hydroxy-2-nonenal (4-HNE) phosphorylated GCN2 and eIF2 α and increased protein levels of ATF4 in a time-dependent manner. (6) siRNA-mediated knockdown of GCN2 abrogated 4-HNE-induced induction of amino acid metabolic genes. [Conclusions] Activation of eIF2 α -ATF4 pathway via GCN2 kinase might be of special importance in the transcriptional control that coordinately promotes amino acid metabolism in response to aldehydes. Intracellular depletion of free histidine is at least partly involved in the activation of GCN2 kinase by aldehydes.

scholarly journals Activation of GCN2 by the ribosomal P-stalk

2019 ◽  
Vol 116 (11) ◽  
pp. 4946-4954 ◽  
Author(s):  
Alison J. Inglis ◽  
Glenn R. Masson ◽  
Sichen Shao ◽  
Olga Perisic ◽  
Stephen H. McLaughlin ◽  
...  
Keyword(s):  
Conformational Changes ◽  
Principal Component ◽  
Protein Translation ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Exchange Mass Spectrometry ◽  
Hydrogen Deuterium ◽  
Hdx Ms ◽  
Ribosomal P

Cells dynamically adjust their protein translation profile to maintain homeostasis in changing environments. During nutrient stress, the kinase general control nonderepressible 2 (GCN2) phosphorylates translation initiation factor eIF2α, initiating the integrated stress response (ISR). To examine the mechanism of GCN2 activation, we have reconstituted this process in vitro, using purified components. We find that recombinant human GCN2 is potently stimulated by ribosomes and, to a lesser extent, by tRNA. Hydrogen/deuterium exchange–mass spectrometry (HDX-MS) mapped GCN2–ribosome interactions to domain II of the uL10 subunit of the ribosomal P-stalk. Using recombinant, purified P-stalk, we showed that this domain of uL10 is the principal component of binding to GCN2; however, the conserved 14-residue C-terminal tails (CTTs) in the P1 and P2 P-stalk proteins are also essential for GCN2 activation. The HisRS-like and kinase domains of GCN2 show conformational changes upon binding recombinant P-stalk complex. Given that the ribosomal P-stalk stimulates the GTPase activity of elongation factors during translation, we propose that the P-stalk could link GCN2 activation to translational stress, leading to initiation of ISR.

scholarly journals Causal Association Between mTOR-Dependent eIF4E mRNA Cap-Dependent Translation and Type 2 Diabetes: A Mendelian Randomization Study (OR31-02-19)

2019 ◽  
Vol 3 (Supplement_1) ◽  
Author(s):  
Ghada Soliman ◽  
C Mary Schooling
Keyword(s):  
Type 2 Diabetes ◽  
Sensitivity Analysis ◽  
Confidence Interval ◽  
Mendelian Randomization ◽  
Protein Translation ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
P Value ◽  
Weighted Median

Abstract Objectives Type 2 diabetes is a prevalent chronic disease and is often associated with obesity and other comorbidities. The mammalian Target of Rapamycin complex 1 (mTORC1) nutrient-signaling pathway is a central regulator of cell growth and metabolism and is dysregulated in chronic diseases including diabetes and obesity. The eukaryotic translation initiation factor 4E (eIF-4E), a key regulator of gene translation and protein function, is under the control of mTOR and eIF4E Binding Proteins (4E-BPs). eIF-4E binds to the m7G (7-methylguanosine) cap at the 5’-UTR of most eukaryotic mRNA and mediates the recruitment of mRNA on ribosomes to start the protein translation. Both 4E-BP and ribosomal protein S6K kinase (S6K) are downstream effectors regulated by mTORC1 but converge to regulate two independent pathways. We investigated whether the risk of type 2 diabetes varied with genetically predicted eIF-4E and S6K levels using Mendelian Randomization (MR). Methods We estimated the causal role of eIF-4E and S6K plasma proteins, mTOR downstream targets, on type 2 diabetes, based on 16 single nucleotide polymorphisms (SNPs) for eIF-4E and 16 SNPs for S6K at P-value < 5x10−6. We applied these SNPs per exposure to publically available genetic associations with diabetes from the DIAbestes Genetics Replication And Meta-analysis (DIAGRAM) case (n = 26,676), and control (n = 132,532) study (mean age 57.4 years). We meta-analyzed SNP-specific Wald estimates using inverse variance weighting with multiplicative random effects. Sensitivity analysis was conducted using the weighted median, and MR-Egger estimates. Results eIF-4E cap-dependent translation factor was associated with lowered risk of type 2 diabetes with an odds ratio (OR) 0.94 per effect size, 95% confidence interval (0.88, 0.99, P = 0.03) with similar estimates from the weighted median and MR-Egger. S6K was not associated with diabetes, OR 0.95, 95% confidence interval (0.89, 1.01, P = 0.08). Sensitivity analysis using MR-Egger and weighed median analysis did not indicate pleiotropic effects suggesting a unique protective effect of eIF-4E on type 2 diabetes. Conclusions This unbiased Mendelian Randomization estimate is consistent with a causally protective association of eIF-4E on type 2 diabetes. eIF-4E may be a target for intervention by repurposing existing therapeutics to reduce the risk of type 2 diabetes. Funding Sources No specific funding.

scholarly journals Measles Virus N Protein Inhibits Host Translation by Binding to eIF3-p40

2007 ◽  
Vol 81 (21) ◽  
pp. 11569-11576 ◽  
Author(s):  
Hiroki Sato ◽  
Munemitsu Masuda ◽  
Moeko Kanai ◽  
Kyoko Tsukiyama-Kohara ◽  
Misako Yoneda ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
Mammalian Cells ◽  
Measles Virus ◽  
Encephalomyocarditis Virus ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Translation System ◽  
Dependent Manner ◽  
Initiation Factors ◽  
Human T Cell

ABSTRACT The nonsegmented, negative-sense RNA genome of measles virus (MV) is encapsidated by the virus-encoded nucleocapsid protein (N). In this study, we searched for N-binding cellular proteins by using MV-N as bait and screening the human T-cell cDNA library by yeast two-hybrid assay and isolated the p40 subunit of eukaryotic initiation factor 3 (eIF3-p40) as a binding partner. The interaction between MV-N and eIF3-p40 in mammalian cells was confirmed by coimmunoprecipitation. Since eIF3-p40 is a translation initiation factor, we analyzed the potential inhibitory effect of MV-N on protein synthesis. Glutathione S-transferase (GST)-fused MV-N (GST-N) inhibited translation of reporter mRNAs in rabbit reticulocyte lysate translation system in a dose-dependent manner. Encephalomyocarditis virus internal ribosomal entry site-mediated translation, which requires canonical initiation factors to initiate translation, was also inhibited by GST-N. In contrast, a unique form of translation mediated by the intergenic region of Plautia stali intestine virus, which can assemble 80S ribosomes in the absence of canonical initiation factors, was scarcely affected by GST-N. In vivo expression of MV-N induced by the Cre/loxP switching system inhibited the synthesis of a transfected reporter protein, as well as overall protein synthesis. These results suggest that MV-N targets eIF3-p40 and may be involved in inhibiting MV-induced host translation.

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