scholarly journals mTOR Controls Cell Cycle Progression through Its Cell Growth Effectors S6K1 and 4E-BP1/Eukaryotic Translation Initiation Factor 4E

2004 ◽  
Vol 24 (1) ◽  
pp. 200-216 ◽  
Author(s):  
Diane C. Fingar ◽  
Celeste J. Richardson ◽  
Andrew R. Tee ◽  
Lynn Cheatham ◽  
Christina Tsou ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Growth ◽  
Cell Cycle Progression ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Wild Type ◽  
Cycle Progression ◽  
Eukaryotic Translation ◽  
Eukaryotic Translation Initiation ◽  
Phase Progression

ABSTRACT The mammalian target of rapamycin (mTOR) integrates nutrient and mitogen signals to regulate cell growth (increased cell mass and cell size) and cell division. The immunosuppressive drug rapamycin inhibits cell cycle progression via inhibition of mTOR; however, the signaling pathways by which mTOR regulates cell cycle progression have remained poorly defined. Here we demonstrate that restoration of mTOR signaling (by using a rapamycin-resistant mutant of mTOR) rescues rapamycin-inhibited G1-phase progression, and restoration of signaling along the mTOR-dependent S6K1 or 4E-BP1/eukaryotic translation initiation factor 4E (eIF4E) pathways provides partial rescue. Furthermore, interfering RNA-mediated reduction of S6K1 expression or overexpression of mTOR-insensitive 4E-BP1 isoforms that block eIF4E activity inhibit G1-phase progression individually and additively. Thus, the activities of both the S6K1 and 4E-BP1/eIF4E pathways are required for and independently mediate mTOR-dependent G1-phase progression. In addition, overexpression of constitutively active mutants of S6K1 or wild-type eIF4E accelerates serum-stimulated G1-phase progression, and stable expression of wild-type S6K1 confers a proliferative advantage in low-serum-containing media, suggesting that the activity of each of these pathways is limiting for cell proliferation. These data demonstrate that, as for the regulation of cell growth and cell size, the S6K1 and 4E-BP1/eIF4E pathways each represent critical mediators of mTOR-dependent cell cycle control.

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 Synthetic mRNAs; Their Analogue Caps and Contribution to Disease

Diseases ◽  
2021 ◽  
Vol 9 (3) ◽  
pp. 57
Author(s):  
Anthony M. Kyriakopoulos ◽  
Peter A. McCullough
Keyword(s):  
Cell Cycle Progression ◽  
Globin Gene ◽  
Mrna Translation ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Transcriptional Level ◽  
Cycle Progression ◽  
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 Cell Cycle Progression and Proliferation Despite 4BP-1 Dephosphorylation

1999 ◽  
Vol 19 (9) ◽  
pp. 6041-6047 ◽  
Author(s):  
Steven O. Marx ◽  
Andrew R. Marks
Keyword(s):  
Cell Cycle ◽  
Translation Initiation ◽  
Cell Cycle Progression ◽  
De Novo ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Similar Degree ◽  
Inhibitory Protein ◽  
Cycle Progression ◽  
Eukaryotic Translation

ABSTRACT Proliferation and cell cycle progression in response to growth factors require de novo protein synthesis. It has been proposed that binding of the eukaryotic translation initiation factor 4E (eIF-4E) to the inhibitory protein 4BP-1 blocks translation by preventing access of eIF-4G to the 5′ cap of the mRNA. The signal for translation initiation is thought to involve phosphorylation of 4BP-1, which causes it to dissociate from eIF-4E and allows eIF-4G to localize to the 5′ cap. It has been suggested that the ability of the macrolide antibiotic rapamycin to inhibit 4BP-1 phosphorylation is responsible for the potent antiproliferative property of this drug. We now show that rapamycin-resistant cells exhibited normal proliferation despite dephosphorylation of 4BP-1 that allows it to bind to eIF-4E. Moreover, despite rapamycin-induced dephosphorylation of 4BP-1, eIF-4E–eIF-4G complexes (eIF-4F) were still detected. In contrast, amino acid withdrawal, which caused a similar degree of 4BP-1 dephosphorylation, resulted in dissociation of the eIF-4E–eIF-4G complex. Thus, 4BP-1 dephosphorylation is not equivalent to eIF-4E inactivation and does not explain the antiproliferative property of rapamycin.

scholarly journals CLN3 expression is sufficient to restore G1-to-S-phase progression in Saccharomyces cerevisiae mutants defective in translation initiation factor eIF4E

1999 ◽  
Vol 340 (1) ◽  
pp. 135-141 ◽  
Author(s):  
Parisa DANAIE ◽  
Michael ALTMANN ◽  
Michael N. HALL ◽  
Hans TRACHSEL ◽  
Stephen B. HELLIWELL
Keyword(s):  
Cell Cycle ◽  
S Phase ◽  
Translation Initiation Factor ◽  
Yeast Cells ◽  
Initiation Factor ◽  
G1 Phase ◽  
Mrna Levels ◽  
Wild Type ◽  
Phase Progression ◽  
Type Gene

The essential cap-binding protein (eIF4E) of Saccharomycescerevisiae is encoded by the CDC33 (wild-type) gene, originally isolated as a mutant, cdc33-1, which arrests growth in the G1 phase of the cell cycle at 37 °C. We show that other cdc33 mutants also arrest in G1. One of the first events required for G1-to-S-phase progression is the increased expression of cyclin 3. Constructs carrying the 5ʹ-untranslated region of CLN3 fused to lacZ exhibit weak reporter activity, which is significantly decreased in a cdc33-1 mutant, implying that CLN3 mRNA is an inefficiently translated mRNA that is sensitive to perturbations in the translation machinery. A cdc33-1 strain expressing either stable Cln3p (Cln3-1p) or a hybrid UBI4 5ʹ-CLN3 mRNA, whose translation displays decreased dependence on eIF4E, arrested randomly in the cell cycle. In these cells CLN2 mRNA levels remained high, indicating that Cln3p activity is maintained. Induction of a hybrid UBI4 5ʹ-CLN3 message in a cdc33-1 mutant previously arrested in G1 also caused entry into a new cell cycle. We conclude that eIF4E activity in the G1-phase is critical in allowing sufficient Cln3p activity to enable yeast cells to enter a new cell cycle.

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 Effects of chronic 5′-{[(Z)-4-amino-2-butenyl]methylamino)-5′-deoxy- adenosine (AbeAdo) treatment on polyamine and eIF-5A metabolism in AbeAdo-sensitive and -resistant L1210 murine leukaemia cells

1993 ◽  
Vol 290 (1) ◽  
pp. 115-121 ◽  
Author(s):  
T L Byers ◽  
L Wiest ◽  
R S Wechter ◽  
A E Pegg
Keyword(s):  
Cell Growth ◽  
Translation Initiation ◽  
Chronic Exposure ◽  
Limit Of Detection ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Eukaryotic Translation ◽  
L1210 Cells ◽  
Eukaryotic Translation Initiation ◽  
Exogenous Spermidine

We have previously reported that prolonged chronic exposure to the S-adenosyl-L-methionine decarboxylase (AdoMetDC) inhibitor, 5′-([(Z)-4-amino-2-butenyl]methylamino)-5′-deoxy-adenosine (MDL 73811, AbeAdo), leads to cytostasis of L1210 cells [Byers, Ganem and Pegg (1992) Biochem. J. 287, 717-724]. Further studies to investigate the mechanism by which these effects are brought about were carried out by comparing an L1210-derived cell line (R20) that is resistant to AbeAdo with the parent cells. The R20 cells were derived by two rounds of AbeAdo-induced cytostasis followed by rescue with exogenous polyamines. Cytostasis was induced in L1210 cells treated for 12 days with 10 microM AbeAdo; however, exposure to up to 40 microM AbeAdo did not induce cytostasis in R20 cells. Putrescine levels were elevated and spermine levels were depleted in both treated L1210 and treated R20 cells. Spermidine was depleted in treated L1210 cells but was only partly reduced in treated R20 cells. AdoMetDC activity was below the limit of detection in treated L1210 cells but, although greatly reduced, could be measured in the treated R20 cells. The resistance of the R20 cells to the effects of AbeAdo on cell growth and spermidine depletion correlated with reduced AbeAdo accumulation by R20 cells. In the absence of spermidine synthesis, unhypusinated eukaryotic translation initiation factor 5A (eIF-5A) accumulated in AbeAdo-treated L1210 cells. There was no detectable accumulation of unhypusinated eIF-5A in R20 cells. Unhypusinated eIF-5A accumulated during AbeAdo treatment was depleted in L1210 cells rescued by exogenous spermidine. These findings are consistent with the hypothesis that AbeAdo-induced cytostasis is due to the loss of hypusinated eIF-5A. However, spermine was able to rescue AbeAdo-treated L1210 cells without significantly reducing the unhypusinated eIF-5A accumulated during AbeAdo treatment, suggesting that only a small amount of the unmodified protein must be hypusinated to restore cell growth.

scholarly journals APOL1 risk variants cause podocytes injury through enhancing endoplasmic reticulum stress

2018 ◽  
Vol 38 (4) ◽  
Author(s):  
Hongxiu Wen ◽  
Vinod Kumar ◽  
Xiqian Lan ◽  
Seyedeh Shadafarin Marashi Shoshtari ◽  
Judith M. Eng ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Kidney Diseases ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Wild Type ◽  
Eukaryotic Translation ◽  
Risk Variants ◽  
Eukaryotic Translation Initiation ◽  
Underlying Mechanisms

Two coding sequence variants (G1 and G2) of Apolipoprotein L1 (APOL1) gene have been implicated as a higher risk factor for chronic kidney diseases (CKD) in African Americans when compared with European Americans. Previous studies have suggested that the APOL1 G1 and G2 variant proteins are more toxic to kidney cells than the wild-type APOL1 G0, but the underlying mechanisms are poorly understood. To determine whether endoplasmic reticulum (ER) stress contributes to podocyte toxicity, we generated human podocytes (HPs) that stably overexpressed APOL1 G0, G1, or G2 (Vec/HPs, G0/HPs, G1/HPs, and G2/HPs). Propidium iodide staining showed that HP overexpressing the APOL1 G1 or G2 variant exhibited a higher rate of necrosis when compared with those overexpressing the wild-type G0 counterpart. Consistently, the expression levels of nephrin and podocin proteins were significantly decreased in the G1- or G2-overexpressing cells despite the maintenance of their mRNA expressions levels. In contrast, the expression of the 78-kDa glucose-regulated protein ((GRP78), also known as the binding Ig protein, BiP) and the phosphorylation of the eukaryotic translation initiation factor 1 (eIF1) were significantly elevated in the G1/HPs and G2/HPs, suggesting a possible occurrence of ER stress in these cells. Furthermore, ER stress inhibitors not only restored nephrin protein expression, but also provided protection against necrosis in G1/HPs and G2/HPs, suggesting that APOL1 risk variants cause podocyte injury partly through enhancing ER stress.

scholarly journals Cancer-Associated Eukaryotic Translation Initiation Factor 1A Mutants Impair Rps3 and Rps10 Binding and Enhance Scanning of Cell Cycle Genes

2018 ◽  
Vol 39 (3) ◽  
Author(s):  
Urmila Sehrawat ◽  
Femke Koning ◽  
Shaked Ashkenazi ◽  
Gil Stelzer ◽  
Dena Leshkowitz ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Translation Initiation ◽  
Ribosome Profiling ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Eukaryotic Translation Initiation Factor ◽  
Eukaryotic Translation ◽  
Cell Cycle Genes ◽  
Eukaryotic Translation Initiation

ABSTRACTProtein synthesis is linked to cell proliferation, and its deregulation contributes to cancer. Eukaryotic translation initiation factor 1A (eIF1A) plays a key role in scanning and AUG selection and differentially affects the translation of distinct mRNAs. Its unstructured N-terminal tail (NTT) is frequently mutated in several malignancies. Here we report that eIF1A is essential for cell proliferation and cell cycle progression. Ribosome profiling of eIF1A knockdown cells revealed a substantial enrichment of cell cycle mRNAs among the downregulated genes, which are predominantly characterized by a lengthy 5′ untranslated region (UTR). Conversely, eIF1A depletion caused a broad stimulation of 5′ UTR initiation at a near cognate AUG, unveiling a prominent role of eIF1A in suppressing 5′ UTR translation. In addition, the AUG context-dependent autoregulation of eIF1 was disrupted by eIF1A depletion, suggesting their cooperation in AUG context discrimination and scanning. Importantly, cancer-associated eIF1A NTT mutants augmented the eIF1A positive effect on a long 5′ UTR, while they hardly affected AUG selection. Mechanistically, these mutations diminished the eIF1A interaction with Rps3 and Rps10 implicated in scanning arrest. Our findings suggest that the reduced binding of eIF1A NTT mutants to the ribosome retains its open state and facilitates scanning of long 5′ UTR-containing cell cycle genes.

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