Cell-autonomous and non-autonomous growth-defective mutants of Drosophila melanogaster

Development ◽  
1999 ◽  
Vol 126 (11) ◽  
pp. 2365-2375 ◽  
Author(s):  
M. Galloni ◽  
B.A. Edgar
Keyword(s):  
Drosophila Melanogaster ◽  
Cell Cycle Progression ◽  
Growth Regulation ◽  
Larval Growth ◽  
The Body ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Tissue Type ◽  
Growth Defect ◽  
Allelic Series

During animal development, growth of the various tissues and organs that make up the body must be coordinated. Despite recent progress in understanding growth control within the cell unit, the mechanisms that coordinate growth at the organismal level are still poorly understood. To study this problem, we performed a genetic screen for larval growth-defective mutants in Drosophila melanogaster. Characterization of these mutants revealed distinct types of larval growth defects. An allelic series for the translation initiation factor, Eif4A, showed different growth rates and suggests that Eif4A could be used as a dose-dependent growth regulator. Two mutants that fail to exit cellular quiescence at larval hatching (milou and eif4(1006)) have a DNA replication block that can be bypassed by overexpression of the E2F transcription factor. A mutation (bonsai) in a homolog of the prokaryotic ribosomal protein, RPS15, causes a growth defect that is non-cell-autonomous. Our results emphasize the importance of translational regulation for the exit from quiescence. They suggest that the level of protein synthesis required for cell cycle progression varies according to tissue type. The isolation of non-cell-autonomous larval growth-defective mutants suggests that specialized organs coordinate growth throughout the animal and provides new tools for studies of organismal growth regulation.

scholarly journals Dual modulation of Ras-Mnk and PI3K-AKT-mTOR pathways: A Novel c-FLIP inhibitory mechanism of 3-AWA mediated translational attenuation through dephosphorylation of eIF4E

2016 ◽  
Vol 6 (1) ◽  
Author(s):  
Reyaz ur Rasool ◽  
Bilal Rah ◽  
Hina Amin ◽  
Debasis Nayak ◽  
Souneek Chakraborty ◽  
...  
Keyword(s):  
Translation Initiation ◽  
Cell Cycle Progression ◽  
De Novo ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Apoptosis Resistance ◽  
Nih3t3 Cells ◽  
Eukaryotic Translation ◽  
Underlying Mechanisms

Abstract The eukaryotic translation initiation factor 4E (eIF4E) is considered as a key survival protein involved in cell cycle progression, transformation and apoptosis resistance. Herein, we demonstrate that medicinal plant derivative 3-AWA (from Withaferin A) suppressed the proliferation and metastasis of CaP cells through abrogation of eIF4E activation and expression via c-FLIP dependent mechanism. This translational attenuation prevents the de novo synthesis of major players of metastatic cascades viz. c-FLIP, c-Myc and cyclin D1. Moreover, the suppression of c-FLIP due to inhibition of translation initiation complex by 3-AWA enhanced FAS trafficking, BID and caspase 8 cleavage. Further ectopically restored c-Myc and GFP-HRas mediated activation of eIF4E was reduced by 3-AWA in transformed NIH3T3 cells. Detailed underlying mechanisms revealed that 3-AWA inhibited Ras-Mnk and PI3-AKT-mTOR, two major pathways through which eIF4E converges upon eIF4F hub. In addition to in vitro studies, we confirmed that 3-AWA efficiently suppressed tumor growth and metastasis in different mouse models. Given that 3-AWA inhibits c-FLIP through abrogation of translation initiation by co-targeting mTOR and Mnk-eIF4E, it (3-AWA) can be exploited as a lead pharmacophore for promising anti-cancer therapeutic development.

scholarly journals Synthetic mRNAs; Their Analogue Caps and Contribution to Disease

2021 ◽  
Author(s):  
Anthony Kyriakopoulos ◽  
Peter McCullough
Keyword(s):  
Cell Cycle Progression ◽  
Globin Gene ◽  
Mrna Translation ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Transcriptional Level ◽  
Beta Globin ◽  
Eukaryotic Translation ◽  
Successful Design ◽  
Eukaryotic Translation Initiation

The structure of synthetic mRNAs as used in vaccination against cancer and infectious diseases contain specifically designed caps followed by sequences of the 5’ untranslated repeats of β-globin gene. The strategy for successful design of synthetic mRNAs by chemically modifying their caps aims to increase resistance to the enzymatic deccapping complex, offer a higher affinity for binding to the eukaryotic translation initiation factor 4E (elF4E) protein and enforce increased translation of their encoded proteins. However, the cellular homeostasis is finely balanced and obeys to specific laws of thermodynamics conferring balance between complexity and growth rate in evolution. An overwhelming and forced translation even under alarming conditions of the cell during a concurrent viral infection, or when molecular pathways are trying to circumvent precursor events that lead to autoimmunity and cancer, may cause the recipient cells to ignore their differential sensitivities which are essential for keeping normal conditions. The elF4E which is a powerful RNA regulon and a potent oncogene governing cell cycle progression and proliferation at a post-transcriptional level, may then be a great contributor to disease development. The mechanistic target of rapamycin (mTOR) axis manly inhibits the elF4E to proceed with mRNA translation but disturbance in fine balances between mTOR and elF4E action may provide a premature step towards oncogenesis, ignite pre-causal mechanisms of immune deregulation and cause maturation (aging) defects.

scholarly journals Hydrogen Indirectly Suppresses Increases in Hydrogen Peroxide in Cytoplasmic Hydroxyl Radical-Induced Cells and Suppresses Cellular Senescence

2019 ◽  
Vol 20 (2) ◽  
pp. 456 ◽  
Author(s):  
Takahiro Sakai ◽  
Ryosuke Kurokawa ◽  
Shin-ichi Hirano ◽  
Jun Imai
Keyword(s):  
Hydrogen Peroxide ◽  
Hydroxyl Radical ◽  
Cellular Senescence ◽  
Physiological Role ◽  
Lipid Peroxide ◽  
Gut Bacteria ◽  
The Body ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Plant Fibers

Bacteria inhabiting the human gut metabolize microbiota-accessible carbohydrates (MAC) contained in plant fibers and subsequently release metabolic products. Gut bacteria produce hydrogen (H2), which scavenges the hydroxyl radical (•OH). Because H2 diffuses within the cell, it is hypothesized that H2 scavenges cytoplasmic •OH (cyto •OH) and suppresses cellular senescence. However, the mechanisms of cyto •OH-induced cellular senescence and the physiological role of gut bacteria-secreted H2 have not been elucidated. Based on the pyocyanin-stimulated cyto •OH-induced cellular senescence model, the mechanism by which cyto •OH causes cellular senescence was investigated by adding a supersaturated concentration of H2 into the cell culture medium. Cyto •OH-generated lipid peroxide caused glutathione (GSH) and heme shortage, increased hydrogen peroxide (H2O2), and induced cellular senescence via the phosphorylation of ataxia telangiectasia mutated kinase serine 1981 (p-ATMser1981)/p53 serine 15 (p-p53ser15)/p21 and phosphorylation of heme-regulated inhibitor (p-HRI)/phospho-eukaryotic translation initiation factor 2 subunit alpha serine 51 (p-eIF2α)/activating transcription factor 4 (ATF4)/p16 pathways. Further, H2 suppressed increased H2O2 by suppressing cyto •OH-mediated lipid peroxide formation and cellular senescence induction via two pathways. H2 produced by gut bacteria diffuses throughout the body to scavenge cyto •OH in cells. Therefore, it is highly likely that gut bacteria-produced H2 is involved in intracellular maintenance of the redox state, thereby suppressing cellular senescence and individual aging. Hence, H2 produced by intestinal bacteria may be involved in the suppression of aging.

scholarly journals S6 Kinase- and β-TrCP2-Dependent Degradation of p19ArfIs Required for Cell Proliferation

2015 ◽  
Vol 35 (20) ◽  
pp. 3517-3527 ◽  
Author(s):  
Tadashi Nakagawa ◽  
Takaaki Araki ◽  
Makiko Nakagawa ◽  
Atsushi Hirao ◽  
Michiaki Unno ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Cell Cycle Progression ◽  
Mammalian Target Of Rapamycin ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Specific Substrate ◽  
S6 Kinase ◽  
Promote Cell Proliferation ◽  
Serum Stimulation ◽  
F Box Protein

The kinase mTOR (mammalian target of rapamycin) promotes translation as well as cell survival and proliferation under nutrient-rich conditions. Whereas mTOR activates translation through ribosomal protein S6 kinase (S6K) and eukaryotic translation initiation factor 4E-binding protein (4E-BP), how it facilitates cell proliferation has remained unclear. We have now identified p19Arf, an inhibitor of cell cycle progression, as a novel substrate of S6K that is targeted to promote cell proliferation. Serum stimulation induced activation of the mTOR-S6K axis and consequent phosphorylation of p19Arfat Ser75. Phosphorylated p19Arfwas then recognized by the F-box protein β-TrCP2 and degraded by the proteasome. Ablation of β-TrCP2 thus led to the arrest of cell proliferation as a result of the stabilization and accumulation of p19Arf. The β-TrCP2 paralog β-TrCP1 had no effect on p19Arfstability, suggesting that phosphorylated p19Arfis a specific substrate of β-TrCP2. Mice deficient in β-TrCP2 manifested accumulation of p19Arfin the yolk sac and diedin utero. Our results suggest that the mTOR pathway promotes cell proliferation via β-TrCP2-dependent p19Arfdegradation under nutrient-rich conditions.

scholarly journals eIF4E is a central node of an RNA regulon that governs cellular proliferation

2006 ◽  
Vol 175 (3) ◽  
pp. 415-426 ◽  
Author(s):  
Biljana Culjkovic ◽  
Ivan Topisirovic ◽  
Lucy Skrabanek ◽  
Melisa Ruiz-Gutierrez ◽  
Katherine L.B. Borden
Keyword(s):  
Cell Cycle ◽  
Messenger Rna ◽  
Cell Cycle Progression ◽  
Cellular Proliferation ◽  
Mrna Export ◽  
Nuclear Bodies ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Eukaryotic Translation ◽  
Eukaryotic Translation Initiation

This study demonstrates that the eukaryotic translation initiation factor eIF4E is a critical node in an RNA regulon that impacts nearly every stage of cell cycle progression. Specifically, eIF4E coordinately promotes the messenger RNA (mRNA) export of several genes involved in the cell cycle. A common feature of these mRNAs is a structurally conserved, ∼50-nucleotide element in the 3′ untranslated region denoted as an eIF4E sensitivity element. This element is sufficient for localization of capped mRNAs to eIF4E nuclear bodies, formation of eIF4E-specific ribonucleoproteins in the nucleus, and eIF4E-dependent mRNA export. The roles of eIF4E in translation and mRNA export are distinct, as they rely on different mRNA elements. Furthermore, eIF4E-dependent mRNA export is independent of ongoing RNA or protein synthesis. Unlike the NXF1-mediated export of bulk mRNAs, eIF4E-dependent mRNA export is CRM1 dependent. Finally, the growth-suppressive promyelocytic leukemia protein (PML) inhibits this RNA regulon. These data provide novel perspectives into the proliferative and oncogenic properties of eIF4E.

scholarly journals The Translation Initiation Factor eIF4E Regulates the Sex-Specific Expression of the Master Switch Gene Sxl in Drosophila melanogaster

PLoS Genetics ◽  
2011 ◽  
Vol 7 (7) ◽  
pp. e1002185 ◽  
Author(s):  
Patricia L. Graham ◽  
Judith L. Yanowitz ◽  
Jill K. M. Penn ◽  
Girish Deshpande ◽  
Paul Schedl
Keyword(s):  
Drosophila Melanogaster ◽  
Translation Initiation ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Specific Expression

scholarly journals Development of Biochemical Assays for the Identification of eIF4E-Specific Inhibitors

2012 ◽  
Vol 17 (5) ◽  
pp. 581-592 ◽  
Author(s):  
Carlo Visco ◽  
Claudia Perrera ◽  
Sandrine Thieffine ◽  
Federico Riccardi Sirtori ◽  
Roberto D’Alessio ◽  
...  
Keyword(s):  
High Throughput Screening ◽  
Cell Cycle Progression ◽  
Critical Role ◽  
Mrna Translation ◽  
Binding Pocket ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Oncogenic Pathways ◽  
Biochemical Assays ◽  
Specific Inhibitors

Control of mRNA translation plays a critical role in cell growth, proliferation, and differentiation and is tightly regulated by AKT and RAS oncogenic pathways. A key player in the regulation of this process is the mRNA 5′ cap-binding protein, eukaryotic translation initiation factor 4E (eIF4E). eIF4E contributes to malignancy by selectively enabling the translation of a limited pool of mRNAs that generally encode key proteins involved in cell cycle progression, angiogenesis, and metastasis. Several data indicate that the inhibition of eIF4E in tumor cell lines and xenograft models impairs tumor growth and induces apoptosis; eIF4E, therefore, can be considered a valuable target for cancer therapy. Targeting the cap-binding pocket of eIF4E should represent a way to inhibit all the eIF4E cellular functions. We present here the development and validation of different biochemical assays based on fluorescence polarization and surface plasmon resonance techniques. These assays could support high-throughput screening, further refinement, and characterization of eIF4E inhibitors, as well as selectivity assessment against CBP80/CBP20, the other major cap-binding complex of eukaryotic cells, overall providing a robust roadmap for development of eIF4E-specific inhibitors.

Localization, structure and expression of the gene for translation initiation factor eIF-4E from Drosophila melanogaster

1997 ◽  
Vol 253 (5) ◽  
pp. 624-633 ◽  
Author(s):  
G. Hernández ◽  
R. Diez del Corral ◽  
J. Santoyo ◽  
S. Campuzano ◽  
J. M. Sierra
Keyword(s):  
Drosophila Melanogaster ◽  
Translation Initiation ◽  
Translation Initiation Factor ◽  
Initiation Factor
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