Acute alcohol intoxication enhances myocardial eIF4G phosphorylation despite reducing mTOR signaling

2005 ◽  
Vol 288 (1) ◽  
pp. H121-H128 ◽  
Author(s):  
Thomas C. Vary ◽  
Gina Deiter ◽  
Stacy A. Goodman
Keyword(s):  
Complex Formation ◽  
Alcohol Intoxication ◽  
Mammalian Target Of Rapamycin ◽  
Mrna Translation ◽  
Mtor Signaling ◽  
Initiation Factor ◽  
Translational Efficiency ◽  
Acute Alcohol Intoxication ◽  
Alcohol Administration ◽  
Mtor Phosphorylation

Acute alcohol intoxication impairs myocardial protein synthesis in rats, secondary to a diminished mRNA translational efficiency. Decreased mRNA translational efficiency occurs through altered regulation of peptide chain initiation. The purpose of the present set of experiments was to determine whether acute alcohol intoxication alters the phosphorylation state of eukaryotic initiation factor (eIF) 4G, eIF4G·eIF4E complex formation, and the mammalian target of rapamycin (mTOR) signaling pathway in the heart. Acute alcohol intoxication was induced by injection of alcohol (75 mmol/kg body wt ip). Control animals received an equal volume of saline. Alcohol administration enhanced phosphorylation of eIF4G (Ser1108) approximately threefold. Alcohol administration lowered formation of the active eIF4G·eIF4E complex by >90%, whereas it increased the abundance of the inactive 4E-binding protein 1 (4E-BP1)·eIF4E complex by ∼160%. Phosphorylation of mTOR on Ser2448 and Ser2481 was decreased by 50%. Reduced mTOR phosphorylation did not result from decreased phosphorylation of PKB. Phosphorylation of 4E-BP1 and S6 kinase 1 (Thr389), downstream targets of mTOR, were also reduced after acute alcohol administration. These data suggest that acute alcohol-induced impairments in myocardial mRNA translation initiation result, in part, from marked decreases in eIF4G·eIF4E complex formation, which appear to be independent of changes in phosphorylation of eIF4G but dependent on mTOR.

scholarly journals Distinct Signaling Events Downstream of mTOR Cooperate To Mediate the Effects of Amino Acids and Insulin on Initiation Factor 4E-Binding Proteins

2005 ◽  
Vol 25 (7) ◽  
pp. 2558-2572 ◽  
Author(s):  
Xuemin Wang ◽  
Anne Beugnet ◽  
Mirei Murakami ◽  
Shinya Yamanaka ◽  
Christopher G. Proud
Keyword(s):  
Amino Acids ◽  
Mammalian Target Of Rapamycin ◽  
Mrna Translation ◽  
Tissue Growth ◽  
Mtor Signaling ◽  
Initiation Factor ◽  
Eukaryotic Initiation Factor 4E ◽  
Terminal Site ◽  
New Strategies

ABSTRACT Signaling through the mammalian target of rapamycin (mTOR) controls cell size and growth as well as other functions, and it is a potential therapeutic target for graft rejection, certain cancers, and disorders characterized by inappropriate cell or tissue growth. mTOR signaling is positively regulated by hormones or growth factors and amino acids. mTOR signaling regulates the phosphorylation of several proteins, the best characterized being ones that control mRNA translation. Eukaryotic initiation factor 4E-binding protein 1 (4E-BP1) undergoes phosphorylation at multiple sites. Here we show that amino acids regulate the N-terminal phosphorylation sites in 4E-BP1 through the RAIP motif in a rapamycin-insensitive manner. Several criteria indicate this reflects a rapamycin-insensitive output from mTOR. In contrast, the insulin-stimulated phosphorylation of the C-terminal site Ser64/65 is generally sensitive to rapamycin, as is phosphorylation of another well-characterized target for mTOR signaling, S6K1. Our data imply that it is unlikely that mTOR directly phosphorylates Thr69/70 in 4E-BP1. Although 4E-BP1 and S6K1 bind the mTOR partner, raptor, our data indicate that the outputs from mTOR to 4E-BP1 and S6K1 are distinct. In cells, efficient phosphorylation of 4E-BP1 requires it to be able to bind to eIF4E, whereas phosphorylation of 4E-BP1 by mTOR in vitro shows no such preference. These data have important implications for understanding signaling downstream of mTOR and the development of new strategies to impair mTOR signaling.

THE INFLUENCE OF VITAMIN C ON EOSINOPHIL RESPONSE TO ACUTE ALCOHOL INTOXICATION IN RATS

1960 ◽  
Vol XXXV (IV) ◽  
pp. 585-593 ◽  
Author(s):  
T. P. J. Vanha-Perttula
Keyword(s):  
Vitamin C ◽  
Ethyl Alcohol ◽  
Intraperitoneal Injection ◽  
Alcohol Intoxication ◽  
Albino Rats ◽  
Acute Alcohol Intoxication ◽  
Alcohol Administration ◽  
Initial Values

ABSTRACT The effect of ethyl alcohol on the circulating eosinophil cells has been studied in female albino rats. An intoxicating dose of alcohol caused a marked depletion of circulating eosinophils which was most clearly evident four hours after the administration of the alcohol. The initial values were not reached before 24 hours had elapsed. Intraperitoneal injection of vitamin C 12 hours prior to the alcohol administration very effectively prevented this eosinopenic reaction. The mechanism of regulation of the eosinophil cells in the circulation has been discussed in the light of previous results and of those obtained in this study.

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 AICAR treatment for 14 days normalizes obesity-induced dysregulation of TORC1 signaling and translational capacity in fasted skeletal muscle

2010 ◽  
Vol 299 (6) ◽  
pp. R1546-R1554 ◽  
Author(s):  
Joshua C. Drake ◽  
Stephen E. Alway ◽  
John M. Hollander ◽  
David L. Williamson
Keyword(s):  
Skeletal Muscle ◽  
Muscle Mass ◽  
Mrna Translation ◽  
Mtor Signaling ◽  
Initiation Factor ◽  
Saline Control ◽  
Obese Mouse ◽  
Peroxisome Proliferator ◽  
Eukaryotic Initiation Factor ◽  
Mouse Skeletal Muscle

The aim of this study was to determine the effect of 14 days of 5-aminoimidazole-4-carboxamide-1β-4-ribofuranoside (AICAR) treatment on mammalian target of rapamycin (mTOR) signaling and mTOR-regulated processes (i.e., translation initiation) in obese mouse skeletal muscle. Our hypothesis was that daily treatment (14 days) with AICAR would normalize obesity-induced alterations in skeletal muscle mTOR signaling and mTOR-regulated processes to lean levels and positively affect muscle mass. Fourteen-week-old male, lean (L; 31.3 g body wt) wild-type and ob/ob (O; 59.6 g body wt) mice were injected with the AMP-activated kinase (AMPK) activator AICAR (A) at 0.5 mg·g body wt−1·day−1 or saline control (C) for 14 days. At 24 h after the last injection (including a 12-h fast), all mice were killed, and the plantar flexor complex muscle (gastrocnemius, soleus, and plantaris) was excised for analysis. Muscle mass was lower in OC (159 ± 12 mg) than LC, LA, and OA (176 ± 10, 178 ± 9, and 166 ± 16 mg, respectively) mice, independent of a body weight change. A decrease in obese muscle mass corresponded with higher muscle cross section staining intensity for lipid and glycogen, higher blood glucose and insulin levels, and lower nuclear-enriched fractions for peroxisome proliferator-activated receptor-γ coactivator-1α protein expression in OC skeletal muscle, which was normalized with AICAR treatment. AMPK and acetyl-cocarboxylase phosphorylation was reduced in OC mice and augmented by AICAR treatment in OA mice. Conversely, OC mice displayed higher activation of downstream targets (S6 kinase-1 and ribosomal protein S6) of mTOR and lower raptor-associated mTOR than LC mice, which were reciprocally altered after 14 days of AICAR treatment. Dysregulation of translational capacity was improved in OA mice, as assessed by sucrose density gradient fractionation of ribosomes, total and ribosome-associated RNA content, eukaryotic initiation factor 4F complex formation, and eukaryotic initiation factor 4G phosphorylation. These data show that short-term (14 days) AMPK agonist treatment augments regulatory processes in atrophic obese mouse skeletal muscle through the normalization of mTOR signaling and mRNA translation closer to lean levels.

L-Leucine Improves the Anemia of the 5q- Syndrome Via Activation of the mTOR (mammalian target of rapamycin) Pathway

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 970-970
Author(s):  
Maria Virgilio ◽  
Elspeth Payne ◽  
Anupama Narla ◽  
Hong Sun ◽  
Barry H. Paw ◽  
...  
Keyword(s):  
Conflicts Of Interest ◽  
Mammalian Target Of Rapamycin ◽  
Macrocytic Anemia ◽  
Flow Cytometric Analysis ◽  
Ribosomal Subunit ◽  
Mrna Translation ◽  
Target Of Rapamycin ◽  
Translational Efficiency ◽  
Erythroid Cells ◽  
Hematopoietic Stem

Abstract Abstract 970 The “5q- syndrome” is a subtype of myelodysplastic syndrome (MDS) characterized by a profound macrocytic anemia that is thought to arise from the heterozygous loss of the RPS14 gene on chromosome 5q. The 5q- syndrome shares many characteristics with another ribosomopathy, Diamond Blackfan anemia (DBA), wherein half the patients have a heterozygous loss of a ribosomal protein gene, with RPS19 being the most frequently mutated. Both RPS19 and RPS14 are components of the 40S small ribosomal subunit. Heterozygous loss of both genes is thought to contribute to the pathophysiology of these ribosomopathies by impairing ribosome function and thereby decreasing mRNA translational efficiency. L-Leucine, a branched-chain amino acid has been shown to be a potent stimulator of mRNA translation. In a case report, administration of L-Leucine to a DBA patient resulted in complete recovery of the anemia and improvement in appetite and growth parameters. We therefore hypothesized that L-Leucine could improve the anemia associated with heterozygous loss of RPS14. To test this hypotheisis, we used zebrafish as an in vivo model for del(5q) MDS. Using antisense morpholinos, we knocked down Rps14 expression to haploinsufficient levels and observed anemia in the resulting morphants. Treatment of these morphants with L-Leucine, but not D-Leuicne, resulted in a dramatic increase in hemoglobinization as well as an increase in total erythroid cells. This observation was further validated in vitro using human CD34+ hematopoietic progenitor cells infected with RPS14 shRNA. Flow cytometric analysis demonstrated that treatment with L-Leucine increased the total number of erythroid cells (glycophorin-A/CD71 expressing cells) compared to untreated cells. In previous studies, L-leucine has been shown to upregulate mRNA translation by activating the mTOR (mammalian target of rapamycin) pathway and its downstream targets S6Kinase (S6K1) and 4E-Binding proteins (4E-BPs). We demonstrated increased levels of phospho-S6K1 as a result of L-Leucine treatment in the rps14 zebrafish morphant embryos. This increased phosphorylation of S6K1 was inhibited by rapamycin, suggesting specificity of mTOR activation in bringing about the L-Leucine effect. In summary, we have successfully demonstrated, in both a zebrafish model and in human primary hematopoietic stem cells, that L-Leucine alleviates the anemia associated with del(5q) MDS. This effect is likely mediated by activation of the mTOR pathway resulting in increased mRNA translation and an improvement in the anemia associated with loss of RPS14. Our studies support the further evaluation of L-Leucine as a potential therapeutic agent in the treatment of the 5q- syndrome. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Effect of acute alcohol intoxication on granulocyte mobilization and kinetics

Blood ◽  
1978 ◽  
Vol 52 (3) ◽  
pp. 551-559
Author(s):  
SJ Gluckman ◽  
RR MacGregor
Keyword(s):  
Bone Marrow ◽  
Heat Loss ◽  
Alcohol Intoxication ◽  
Acute Alcohol Intoxication ◽  
Endotoxin Administration ◽  
Alcohol Administration ◽  
Human Volunteers ◽  
Normal Controls ◽  
Bone Marrow Granulocytes

Granulocyte mobilization into skin abrasions in human volunteers was significantly inhibited by acute alcohol intoxication (45,-800 cells in 8 hr versus 353,000 in normal controls). Alcohol applied locally did not inhibit granulocyte delivery, and protection of the abrasion against heat loss did not reduce the inhibited delivery in intoxicated volunteers. Intoxication inhibited granulocyte adherence and local mobilization in parallel. Alcohol administration to rabbits shifted granulocytes from marginal to circulating pool in a manner similar to epinephrine. Mobilization of bone marrow granulocytes by glucocorticoid or endotoxin administration was not inhibited by intoxication, nor did it prevent the endotoxin-induced shift of granulocytes from circulating to marginal pool.

Tissue-specific regulation of protein synthesis by insulin and free fatty acids

2003 ◽  
Vol 285 (4) ◽  
pp. E754-E762 ◽  
Author(s):  
Stephen J. Crozier ◽  
Joshua C. Anthony ◽  
Charles M. Schworer ◽  
Ali K. Reiter ◽  
Tracy G. Anthony ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
Translational Control ◽  
Mammalian Target Of Rapamycin ◽  
Diabetic Rats ◽  
Mtor Signaling ◽  
Initiation Factor ◽  
Energy Status ◽  
Cellular Energy ◽  
Specific Regulation ◽  
Induced Changes

The purpose of the study described herein was to investigate how the mammalian target of rapamycin (mTOR)-signaling pathway and eukaryotic initiation factor 2B (eIF2B) activity, both having key roles in the translational control of protein synthesis in skeletal muscle, are regulated in cardiac muscle of rats in response to two different models of altered free fatty acid (FFA) and insulin availability. Protein synthetic rates were reduced in both gastrocnemius and heart of 3-day diabetic rats. The reduction was associated with diminished mTOR-mediated signaling and eIF2B activity in the gastrocnemius but only with diminished mTOR signaling in the heart. In response to the combination of acute hypoinsulinemia and hypolipidemia induced by administration of niacin, protein synthetic rates were also diminished in both gastrocnemius and heart. The niacin-induced changes were associated with diminished mTOR signaling and eIF2B activity in the heart but only with decreased mTOR signaling in the gastrocnemius. In the heart, mTOR signaling and eIF2B activity correlated with cellular energy status and/or redox potential. Thus FFAs may contribute to the translational control of protein synthesis in the heart but not in the gastrocnemius. In contrast, insulin, but not FFAs, is required for the maintenance of protein synthesis in the gastrocnemius.

Translational Control Through the eIF4E Binding Proteins in the Brain

2018 ◽  
Author(s):  
Argel Aguilar-Valles ◽  
Edna Matta-Camacho ◽  
Nahum Sonenberg
Keyword(s):  
Translational Control ◽  
Messenger Rna ◽  
Binding Proteins ◽  
Depressive Disorders ◽  
Mammalian Target Of Rapamycin ◽  
Mrna Translation ◽  
Initiation Factor ◽  
Eukaryotic Initiation Factor 4E ◽  
Initiation Step ◽  
The Brain

Translation of messenger RNA (mRNA) into protein (protein synthesis) is a highly regulated process that controls gene expression. Various signaling pathways, including the mammalian target of rapamycin (mTOR), control mRNA translation at the initiation step. mTOR is part of a multi-subunit complex that regulates mRNA translation initiation by phosphorylating and inactivating the eukaryotic initiation factor 4E binding proteins (4E-BPs). 4E-BPs are a central mechanism in the control of cap-dependent translation in the brain. This chapter reviews the involvement of the 4E-BPs, particularly 4E-BP2, in brain development and synaptic transmission. Furthermore, it discusses the involvement of 4E-BP2 in autistic-like alterations, learning and memory, circadian rhythm regulation, and its roles in the pathophysiology and treatment of psychiatric (depressive disorders, schizophrenia) and neurodegenerative disorders (Parkinson’s).

Effects of chronic alcohol consumption on regulation of myocardial protein synthesis

2001 ◽  
Vol 281 (3) ◽  
pp. H1242-H1251 ◽  
Author(s):  
Thomas C. Vary ◽  
Christopher J. Lynch ◽  
Charles H. Lang
Keyword(s):  
Protein Synthesis ◽  
Mammalian Target Of Rapamycin ◽  
Alcohol Exposure ◽  
Inhibitory Effect ◽  
Initiation Factor ◽  
Heart Weight ◽  
Ethanol Administration ◽  
Translational Efficiency ◽  
Chronic Alcohol ◽  
Protein Mass

Heart disease represents an important etiology of mortality in chronic alcoholics. The purpose of the present study was to examine potential mechanisms for the inhibitory effect of chronic alcohol exposure (16 wk) on the regulation of myocardial protein metabolism. Chronic alcohol feeding resulted in a lower heart weight and 25% loss of cardiac protein per heart compared with pair-fed controls. The loss of protein mass resulted in part from a diminished (30%) rate of protein synthesis. Ethanol exerted its inhibition of protein synthesis through diminished translational efficiency rather than lower RNA content. Chronic ethanol administration decreased the abundance of eukaryotic initiation factor (eIF)4G associated with eIF4E in the myocardium by 36% and increased the abundance of the translation response protein (4E-BP1) associated with eIF4E. In addition, chronic alcohol feeding significantly reduced the extent of p70S6 kinase (p70S6K) phosphorylation. The decreases in the phosphorylation of 4E-BP1 and p70S6K did not result from a reduced abundance of mammalian target of rapamycin (mTOR). These data suggest that a chronic alcohol-induced impairment in myocardial protein synthesis results in part from inhibition in peptide chain initiation secondary to marked changes in eIF4E availability and p70S6Kphosphorylation.

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.

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