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 Stat1 stimulates cap-independent mRNA translation to inhibit cell proliferation and promote survival in response to antitumor drugs

2015 ◽  
Vol 112 (17) ◽  
pp. E2149-E2155 ◽  
Author(s):  
Shuo Wang ◽  
Christos Patsis ◽  
Antonis E. Koromilas
Keyword(s):  
Cell Proliferation ◽  
Kinase Inhibitor ◽  
Binding Protein ◽  
Mammalian Target Of Rapamycin ◽  
Mrna Translation ◽  
B Cell Lymphoma ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Translational Repressor ◽  
Antiapoptotic Proteins

The signal transducer and activator of transcription 1 (Stat1) functions as a tumor suppressor via immune regulatory and cell-autonomous pathways. Herein, we report a previously unidentified cell-autonomous Stat1 function, which is its ability to exhibit both antiproliferative and prosurvival properties by facilitating translation of mRNAs encoding for the cyclin-dependent kinase inhibitor p27Kip1 and antiapoptotic proteins X-linked inhibitor of apoptosis and B-cell lymphoma xl. Translation of the select mRNAs requires the transcriptional function of Stat1, resulting in the up-regulation of the p110γ subunit of phosphoinositide 3-kinase (PI3K) class IB and increased expression of the translational repressor translation initiation factor 4E (eIF4E)-binding protein 1 (4EBP1). Increased PI3Kγ signaling promotes the degradation of the eIF4A inhibitor programmed cell death protein 4, which favors the cap-independent translation of the select mRNAs under conditions of general inhibition of protein synthesis by up-regulated eIF4E-binding protein 1. As such, Stat1 inhibits cell proliferation but also renders cells increasingly resistant to antiproliferative effects of pharmacological inhibitors of PI3K and/or mammalian target of rapamycin. Stat1 also protects Ras-transformed cells from the genotoxic effects of doxorubicin in culture and immune-deficient mice. Our findings demonstrate an important role of mRNA translation in the cell-autonomous Stat1 functions, with implications in tumor growth and treatment with chemotherapeutic drugs.

scholarly journals S6 kinase 1 knockout inhibits uninephrectomy- or diabetes-induced renal hypertrophy

2009 ◽  
Vol 297 (3) ◽  
pp. F585-F593 ◽  
Author(s):  
Jian-Kang Chen ◽  
Jianchun Chen ◽  
George Thomas ◽  
Sara C. Kozma ◽  
Raymond C. Harris
Keyword(s):  
Mammalian Target Of Rapamycin ◽  
Cell Number ◽  
Northern Blotting ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Wild Type ◽  
Minimal Cell ◽  
Renal Hypertrophy ◽  
S6 Kinase ◽  
Compensatory Renal Hypertrophy

Removal of one kidney stimulates synthesis of RNA and protein, with minimal DNA replication, in all nephron segments of the remaining kidney, resulting in cell growth (increase in cell size) with minimal cell proliferation (increase in cell number). In addition to the compensatory renal hypertrophy caused by nephron loss, pathophysiological renal hypertrophy can occur as a consequence of early uncontrolled diabetes. However, the molecular mechanism underlying renal hypertrophy in these conditions remains unclear. In the present study, we report that deletion of S6 kinase 1 (S6K1) inhibited renal hypertrophy seen following either contralateral nephrectomy or induction of diabetes. In wild-type mice, hypertrophic stimuli increased phosphorylation of 40S ribosomal protein S6 (rpS6), a known target of S6K1. Immunoblotting analysis revealed that S6K1−/− mice exhibited moderately elevated basal levels of rpS6, which did not increase further in response to the hypertrophic stimuli. Northern blotting indicated a moderate upregulation of S6K2 expression in the kidneys of S6K1−/− mice. Phosphorylation of the eukaryotic translation initiation factor 4E-binding protein 1, another downstream target of the mammalian target of rapamycin (mTOR), was stimulated to equivalent levels in S6K1−/− and S6K1+/+ littermates during renal hypertrophy, indicating that mTOR was still activated in the S6K1−/− mice. The highly selective mTOR inhibitor, rapamycin, inhibited increased phosphorylation of rpS6 and blocked 60–70% of the hypertrophy seen in wild-type mice but failed to prevent the ∼10% hypertrophy seen in S6K1−/− mice in response to uninephrectomy (UNX) although it did inhibit the basal rpS6 phosphorylation. Thus the present study provides the first genetic evidence that S6K1 plays a major role in the development of compensatory renal hypertrophy as well as diabetic renal hypertrophy and indicates that UNX- and diabetes-mediated mTOR activation can selectively activate S6K1 without activating S6K2.

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 Control of Paip1-Eukayrotic Translation Initiation Factor 3 Interaction by Amino Acids through S6 Kinase

2014 ◽  
Vol 34 (6) ◽  
pp. 1046-1053 ◽  
Author(s):  
Y. Martineau ◽  
X. Wang ◽  
T. Alain ◽  
E. Petroulakis ◽  
D. Shahbazian ◽  
...  
Keyword(s):  
Amino Acids ◽  
Translation Initiation ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
S6 Kinase ◽  
Translation Initiation Factor 3

scholarly journals 4E-BP2–dependent translation in parvalbumin neurons controls epileptic seizure threshold

2021 ◽  
Vol 118 (15) ◽  
pp. e2025522118
Author(s):  
Vijendra Sharma ◽  
Rapita Sood ◽  
Danning Lou ◽  
Tzu-Yu Hung ◽  
Maxime Lévesque ◽  
...  
Keyword(s):  
Animal Models ◽  
Mammalian Target Of Rapamycin ◽  
Neuronal Cell ◽  
Mrna Translation ◽  
Translation Initiation Factor ◽  
Inhibitory Neurons ◽  
Initiation Factor ◽  
Seizure Threshold ◽  
Parvalbumin Neurons

The mechanistic/mammalian target of rapamycin complex 1 (mTORC1) integrates multiple signals to regulate critical cellular processes such as mRNA translation, lipid biogenesis, and autophagy. Germline and somatic mutations in mTOR and genes upstream of mTORC1, such as PTEN, TSC1/2, AKT3, PIK3CA, and components of GATOR1 and KICSTOR complexes, are associated with various epileptic disorders. Increased mTORC1 activity is linked to the pathophysiology of epilepsy in both humans and animal models, and mTORC1 inhibition suppresses epileptogenesis in humans with tuberous sclerosis and animal models with elevated mTORC1 activity. However, the role of mTORC1-dependent translation and the neuronal cell types mediating the effect of enhanced mTORC1 activity in seizures remain unknown. The eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1) and 2 (4E-BP2) are translational repressors downstream of mTORC1. Here we show that the ablation of 4E-BP2, but not 4E-BP1, in mice increases the sensitivity to pentylenetetrazole (PTZ)- and kainic acid (KA)–induced seizures. We demonstrate that the deletion of 4E-BP2 in inhibitory, but not excitatory neurons, causes an increase in the susceptibility to PTZ-induced seizures. Moreover, mice lacking 4E-BP2 in parvalbumin, but not somatostatin or VIP inhibitory neurons exhibit a lowered threshold for seizure induction and reduced number of parvalbumin neurons. A mouse model harboring a human PIK3CA mutation that enhances the activity of the PI3K-AKT pathway (Pik3caH1047R-Pvalb) selectively in parvalbumin neurons shows susceptibility to PTZ-induced seizures. Our data identify 4E-BP2 as a regulator of epileptogenesis and highlight the central role of increased mTORC1-dependent translation in parvalbumin neurons in the pathophysiology of epilepsy.

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 Ku-0063794 is a specific inhibitor of the mammalian target of rapamycin (mTOR)

2009 ◽  
Vol 421 (1) ◽  
pp. 29-42 ◽  
Author(s):  
Juan M. García-Martínez ◽  
Jennifer Moran ◽  
Rosemary G. Clarke ◽  
Alex Gray ◽  
Sabina C. Cosulich ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Cell Growth ◽  
Mammalian Target Of Rapamycin ◽  
Specific Inhibitor ◽  
Initiation Factor ◽  
Target Of Rapamycin ◽  
S6 Kinase ◽  
Class 1 ◽  
Hydrophobic Motif ◽  
Ribosomal S6 Kinase

mTOR (mammalian target of rapamycin) stimulates cell growth by phosphorylating and promoting activation of AGC (protein kinase A/protein kinase G/protein kinase C) family kinases such as Akt (protein kinase B), S6K (p70 ribosomal S6 kinase) and SGK (serum and glucocorticoid protein kinase). mTORC1 (mTOR complex-1) phosphorylates the hydrophobic motif of S6K, whereas mTORC2 phosphorylates the hydrophobic motif of Akt and SGK. In the present paper we describe the small molecule Ku-0063794, which inhibits both mTORC1 and mTORC2 with an IC50 of ∼10 nM, but does not suppress the activity of 76 other protein kinases or seven lipid kinases, including Class 1 PI3Ks (phosphoinositide 3-kinases) at 1000-fold higher concentrations. Ku-0063794 is cell permeant, suppresses activation and hydrophobic motif phosphorylation of Akt, S6K and SGK, but not RSK (ribosomal S6 kinase), an AGC kinase not regulated by mTOR. Ku-0063794 also inhibited phosphorylation of the T-loop Thr308 residue of Akt phosphorylated by PDK1 (3-phosphoinositide-dependent protein kinase-1). We interpret this as implying phosphorylation of Ser473 promotes phosphorylation of Thr308 and/or induces a conformational change that protects Thr308 from dephosphorylation. In contrast, Ku-0063794 does not affect Thr308 phosphorylation in fibroblasts lacking essential mTORC2 subunits, suggesting that signalling processes have adapted to enable Thr308 phosphorylation to occur in the absence of Ser473 phosphorylation. We found that Ku-0063794 induced a much greater dephosphorylation of the mTORC1 substrate 4E-BP1 (eukaryotic initiation factor 4E-binding protein 1) than rapamycin, even in mTORC2-deficient cells, suggesting a form of mTOR distinct from mTORC1, or mTORC2 phosphorylates 4E-BP1. Ku-0063794 also suppressed cell growth and induced a G1-cell-cycle arrest. Our results indicate that Ku-0063794 will be useful in delineating the physiological roles of mTOR and may have utility in treatment of cancers in which this pathway is inappropriately activated.

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 LncRNA GASAL1 Interacts with SRSF1 to Regulate Trophoblast Cell Proliferation, Invasion, and Apoptosis Via the mTOR Signaling Pathway

2020 ◽  
Vol 29 ◽  
pp. 096368972096518
Author(s):  
Jia Liu ◽  
Qing Zhang ◽  
Nan Ma
Keyword(s):  
Cell Proliferation ◽  
Signaling Pathway ◽  
Mammalian Target Of Rapamycin ◽  
Potential Interaction ◽  
Trophoblast Cell ◽  
Mtor Signaling ◽  
Mtor Signaling Pathway ◽  
Promote Cell Proliferation ◽  
Proliferation And Invasion ◽  
Jar Cells

Long noncoding RNAs (lncRNAs) are crucial regulatory molecules involved in diverse biological processes and human diseases, including preeclampsia (PE). The lncRNA growth arrest associated lncRNA 1 (GASAL1) has been implicated in multiple malignant solid tumors and other diseases, while it is poorly known as the potential molecular mechanism of GASAL1 in PE. In this study, GASAL1 was significantly downregulated in the placentas’ of tissues from primipara with PE and trophoblast cell lines. Then, the upregulation of GASAL1 dramatically decreased proliferation and invasion and enhanced apoptosis in HTR-8/SVneo and JAR cells. Bioinformatics tool predicated that there is a potential interaction between GASAL1 and serine/arginine splicing factor 1 (SRSF1). RNA pull-down assays showed that GASAL1 directly binds with SRSF1 that could promote cell proliferation and invasion and suppress cell apoptosis. Further research showed that promoting effects of trophoblasts proliferation and invasion caused by co-transfecting GASAL1 and SRSF1 into HTR-8/SVneo and JAR cells were impaired by SRSF1 knockdown. Moreover, inhibition of the mammalian target of rapamycin (mTOR) activity by rapamycin influenced the effects of GASAL1 on cell proliferation, invasion, and apoptosis. Taken together, these findings suggest that lncRNA GASAL1 interacts with SRSF1 to regulate the proliferative, invasive, and apoptotic abilities of trophoblast cells via the mTOR signaling pathway.

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