scholarly journals The Immunosuppressant Rapamycin Mimics a Starvation-Like Signal Distinct from Amino Acid and Glucose Deprivation

2002 ◽  
Vol 22 (15) ◽  
pp. 5575-5584 ◽  
Author(s):  
Tao Peng ◽  
Todd R. Golub ◽  
David M. Sabatini
Keyword(s):  
Amino Acids ◽  
Amino Acid ◽  
Transcriptional Profiling ◽  
Mammalian Target Of Rapamycin ◽  
Glucose Deprivation ◽  
Amino Acid Deprivation ◽  
Nucleotide Synthesis ◽  
Rapamycin Treatment ◽  
B Lymphoma Cells ◽  
Nutrient Use

ABSTRACT RAFT1/FRAP/mTOR is a key regulator of cell growth and division and the mammalian target of rapamycin, an immunosuppressive and anticancer drug. Rapamycin deprivation and nutrient deprivation have similar effects on the activity of S6 kinase 1 (S6K1) and 4E-BP1, two downstream effectors of RAFT1, but the relationship between nutrient- and rapamycin-sensitive pathways is unknown. Using transcriptional profiling, we show that, in human BJAB B-lymphoma cells and murine CTLL-2 T lymphocytes, rapamycin treatment affects the expression of many genes involved in nutrient and protein metabolism. The rapamycin-induced transcriptional profile is distinct from those induced by glucose, glutamine, or leucine deprivation but is most similar to that induced by amino acid deprivation. In particular, rapamycin treatment and amino acid deprivation up-regulate genes involved in nutrient catabolism and energy production and down-regulate genes participating in lipid and nucleotide synthesis and in protein synthesis, turnover, and folding. Surprisingly, however, rapamycin had effects opposite from those of amino acid starvation on the expression of a large group of genes involved in the synthesis, transport, and use of amino acids. Supported by measurements of nutrient use, the data suggest that RAFT1 is an energy and nutrient sensor and that rapamycin mimics a signal generated by the starvation of amino acids but that the signal is unlikely to be the absence of amino acids themselves. These observations underscore the importance of metabolism in controlling lymphocyte proliferation and offer a novel explanation for immunosuppression by rapamycin.

scholarly journals A Novel Mechanism for the Control of Translation Initiation by Amino Acids, Mediated by Phosphorylation of Eukaryotic Initiation Factor 2B

2007 ◽  
Vol 28 (5) ◽  
pp. 1429-1442 ◽  
Author(s):  
Xuemin Wang ◽  
Christopher G. Proud
Keyword(s):  
Amino Acids ◽  
Protein Synthesis ◽  
Amino Acid ◽  
Translation Initiation ◽  
Mammalian Target Of Rapamycin ◽  
Mrna Translation ◽  
Initiation Factor ◽  
Eukaryotic Initiation Factor ◽  
Amino Acid Deprivation ◽  
Signaling Mechanism

ABSTRACT Eukaryotic initiation factor 2B (eIF2B) plays a key role in controlling the initiation of mRNA translation. eIF2B is heteropentamer whose catalytic (ε) subunit promotes GDP/GTP exchange on eIF2. We show here that depriving human cells of amino acids rapidly results in the inhibition of eIF2B, independently of changes in eIF2 phosphorylation. Although amino acid deprivation also inhibits signaling through the mammalian target of rapamycin complex 1 (mTORC1), the inhibition of eIF2B activity by amino acid starvation is independent of mTORC1. Instead, amino acids repress the phosphorylation of a novel site in eIF2Bε. We identify this site as Ser525, located adjacent to the known phosphoregulatory region in eIF2Bε. Mutation of Ser525 to Ala abolishes the regulation of eIF2B and protein synthesis by amino acids. This indicates that phosphorylation of this site is crucial for the control of eIF2B and protein synthesis by amino acids. These findings identify a new way in which amino acids regulate a key step in translation initiation and indicate that this involves a novel amino acid-sensitive signaling mechanism.

scholarly journals Amino acid deprivation induces AKT activation by inducing GCN2/ATF4/REDD1 axis

2021 ◽  
Vol 12 (12) ◽  
Author(s):  
Hyeon-Ok Jin ◽  
Sung-Eun Hong ◽  
Ji-Young Kim ◽  
Se-Kyeong Jang ◽  
In-Chul Park
Keyword(s):  
Amino Acids ◽  
Amino Acid ◽  
Cell Survival ◽  
Amino Acid Deprivation ◽  
General Control ◽  
Akt Activation ◽  
Amino Acid Availability ◽  
Survival Signal ◽  
Cancer Cell Survival ◽  
Glutamine Deprivation

AbstractAmino acid availability is sensed by various signaling molecules, including general control nonderepressible 2 (GCN2) and mechanistic target of rapamycin complex 1 (mTORC1). However, it is unclear how these sensors are associated with cancer cell survival under low amino acid availability. In the present study, we investigated AKT activation in non-small cell lung cancer (NSCLC) cells deprived of each one of 20 amino acids. Among the 20 amino acids, deprivation of glutamine, arginine, methionine, and lysine induced AKT activation. AKT activation was induced by GCN2/ATF4/REDD1 axis-mediated mTORC2 activation under amino acid deprivation. In CRISPR-Cas9-mediated REDD1-knockout cells, AKT activation was not induced by amino acid deprivation, indicating that REDD1 plays a major role in AKT activation under amino acid deprivation. Knockout of REDD1 sensitized cells cultured under glutamine deprivation conditions to radiotherapy. Taken together, GCN2/ATF4/REDD1 axis induced by amino acid deprivation promotes cell survival signal, which might be a potential target for cancer therapy.

Effect of amino acid deprivation on initiation of protein synthesis in rat hepatocytes

1989 ◽  
Vol 256 (1) ◽  
pp. C18-C27 ◽  
Author(s):  
W. V. Everson ◽  
K. E. Flaim ◽  
D. M. Susco ◽  
S. R. Kimball ◽  
L. S. Jefferson
Keyword(s):  
Amino Acids ◽  
Protein Synthesis ◽  
Amino Acid ◽  
Rat Hepatocytes ◽  
Initiation Factor ◽  
Synthetic Activity ◽  
Perfused Liver ◽  
Amino Acid Deprivation ◽  
Isolated Rat Hepatocytes ◽  
Reticulocyte Lysate

Conditions were defined for maintaining optimal protein synthetic activity in suspensions of freshly isolated rat hepatocytes. Under these conditions, isolated hepatocytes exhibited rates of protein synthesis and levels of polysomal aggregation equivalent to those observed in vivo and in perfused liver. Deprivation of total amino acids or single, essential amino acids resulted in a rapid decrease in the rate of protein synthesis, which was readily reversed by readdition of the deficient amino acid(s). The decrease was accompanied by a disaggregation of polysomes and an inhibition of 43S initiation complex formation, which was indicative of a limitation in the rate of initiation of protein synthesis. Extracts prepared from perfused liver deprived of amino acids were inhibitory to initiation of protein synthesis in reticulocyte lysate. The inhibition in reticulocyte lysate was accompanied by an increase in phosphorylation of the alpha-subunit of eukaryotic initiation factor 2 (eIF-2), suggesting activation of an eIF-2 alpha kinase or inhibition of a phosphatase in amino acid-deprived hepatocytes. This suggestion was confirmed by prelabeling hepatocytes with 32Pi before amino acid deprivation. Incorporation of 32Pi into eIF-2 alpha was two- to threefold higher in lysine-deprived cells than in hepatocytes incubated in fully supplemented medium. Overall, the results indicated that an increase in eIF-2 alpha phosphorylation was responsible for the defect in initiation of protein synthesis caused by amino acid deprivation.

scholarly journals Turnover as a control of ribonucleic acid accumulation in bacteria undergoing stepdown

1976 ◽  
Vol 154 (2) ◽  
pp. 541-552
Author(s):  
J E. M. Midgley
Keyword(s):  
Amino Acids ◽  
Amino Acid ◽  
Turnover Rate ◽  
Amino Acid Starvation ◽  
High Rate ◽  
Glucose Medium ◽  
Amino Acid Deprivation ◽  
Acid Accumulation ◽  
Associated Proteins ◽  
Kinetics Of

The synthesis of ribosomes was compared in rel+ and rel- strains of Escherichia coli undergoing “stepdown” in growth from glucose medium to one with lactate as principal carbon source. Two strains (CP78 and CP79), isogenic except for rel, showed similar behaviour with respect to (1) the kinetics of labelling total RNA and ribosomes with exogenous uracil, (2) the proportion of newly formed protein that could be bound with nascent rRNA in mature ribosomes, and (3) the rate of induction of enzymically active β-galactosidase (relative to the rate of ribosome synthesis). It was concluded that, as there was no net accumulation of RNA during stepdown in either strain, rRNA turnover must be occurring at a high rate. The general features of ribosome maturation in rel+ and rel- cells were almost identical with those found in auxotrophic rel+ organisms starved of required amino acids. In both cases, there was a considerable delay in the maturation of new ribosomal particles, owing to a relative shortfall in the rate of synthesis of ribosome-associated proteins. Only about 4-5% of the total protein labelled during stepdown was capable of binding with newly formed rRNA. This compared with 3.5% for rel+ and 0.5% for rel- auxotrophs during amino acid starvation. The turnover rate for newly formed mRNA and rRNA was virtually the same in “stepped-down” rel+ and rel- strains and was similar to that of the same fraction in amino acid-starved rel+ cells. The functional lifetime of mRNA was also identical. It seems that in the rel- strain many of the characteristics typical of the isogenic rel+ strain are displayed under these conditions, at least as regards the speed of ribosome maturation and the induction of β-galactosidase. Studies on the thermolability of the latter enzyme induced during stepdown indicate that inaccurate translation, which occurs in rel- strains starved for only a few amino acids, is less evident in this situation than in straightforward amino acid deprivation.

Amino acids and mTOR signalling in anabolic function

2007 ◽  
Vol 35 (5) ◽  
pp. 1187-1190 ◽  
Author(s):  
C.G. Proud
Keyword(s):  
Amino Acids ◽  
Amino Acid ◽  
Tuberous Sclerosis ◽  
Tuberous Sclerosis Complex ◽  
Ribosome Biogenesis ◽  
Mammalian Target Of Rapamycin ◽  
Single Amino Acid ◽  
Translational Machinery ◽  
Intracellular Amino Acids ◽  
Mtor Signalling

Amino acids regulate signalling through the mTORC1 (mammalian target of rapamycin, complex 1) and thereby control a number of components of the translational machinery, including initiation and elongation factors. mTORC1 also positively regulates other anabolic processes, in particular ribosome biogenesis. The most effective single amino acid is leucine. A key issue is how intracellular amino acids regulate mTORC1. This does not require the TSC1/2 (tuberous sclerosis complex 1/2) complex, which is involved in the activation of mTORC1, for example, by insulin. Progress in understanding the mechanisms responsible for this will be reviewed.

scholarly journals Amino acid sensing and mTOR regulation: inside or out?

2009 ◽  
Vol 37 (1) ◽  
pp. 248-252 ◽  
Author(s):  
Deborah C.I. Goberdhan ◽  
Margret H. Ögmundsdóttir ◽  
Shubana Kazi ◽  
Bruno Reynolds ◽  
Shivanthy M. Visvalingam ◽  
...  
Keyword(s):  
Amino Acids ◽  
Amino Acid ◽  
Growth Factor ◽  
Environmental Conditions ◽  
Detection System ◽  
Mammalian Target Of Rapamycin ◽  
Target Of Rapamycin ◽  
Amino Acid Sensing ◽  
The Impact ◽  
Mtor Signalling

mTOR (mammalian target of rapamycin) plays a key role in determining how growth factor, nutrient and oxygen levels modulate intracellular events critical for the viability and growth of the cell. This is reflected in the impact of aberrant mTOR signalling on a number of major human diseases and has helped to drive research to understand how TOR (target of rapamycin) is itself regulated. While it is clear that amino acids can affect TOR signalling, how these molecules are sensed by TOR remains controversial, perhaps because cells use different mechanisms as environmental conditions change. Even the question of whether they have an effect inside the cell or at its surface remains unresolved. The present review summarizes current ideas and suggests ways in which some of the models proposed might be unified to produce an amino acid detection system that can adapt to environmental change.

Rheb and Rags come together at the lysosome to activate mTORC1

2013 ◽  
Vol 41 (4) ◽  
pp. 951-955 ◽  
Author(s):  
Marlous J. Groenewoud ◽  
Fried J.T. Zwartkruis
Keyword(s):  
Amino Acids ◽  
Growth Factors ◽  
Amino Acid ◽  
Cell Growth ◽  
Mammalian Target Of Rapamycin ◽  
Maturation Process ◽  
Phospholipase D1 ◽  
Strict Requirement ◽  
Mtorc1 Activation ◽  
Dependent Interaction

mTORC1 (mammalian target of rampamycin complex 1) is a highly conserved protein complex regulating cell growth and metabolism via its kinase mTOR (mammalian target of rapamycin). The activity of mTOR is under the control of various GTPases, of which Rheb and the Rags play a central role. The presence of amino acids is a strict requirement for mTORC1 activity. The heterodimeric Rag GTPases localize mTORC1 to lysosomes by their amino-acid-dependent interaction with the lysosomal Ragulator complex. Rheb is also thought to reside on lysosomes to activate mTORC1. Rheb is responsive to growth factors, but, in conjunction with PLD1 (phospholipase D1), is also an integral part of the machinery that stimulates mTORC1 in response to amino acids. In the present article, we provide a brief overview of novel mechanisms by which amino acids affect the function of Rags. On the basis of existing literature, we postulate that Rheb is activated at the Golgi from where it will travel to lysosomes. Maturation of endosomes into lysosomes may be required to assure a continuous supply of GTP-bound Rheb for mTORC1 activation, which may help to drive the maturation process.

Beclin 1 self-association is independent of autophagy induction by amino acid deprivation and rapamycin treatment

2010 ◽  
Vol 110 (5) ◽  
pp. 1262-1271 ◽  
Author(s):  
Shelly Adi-Harel ◽  
Shlomit Erlich ◽  
Eran Schmukler ◽  
Sarit Cohen-Kedar ◽  
Oshik Segev ◽  
...  
Keyword(s):  
Amino Acid ◽  
Beclin 1 ◽  
Amino Acid Deprivation ◽  
Rapamycin Treatment ◽  
Autophagy Induction ◽  
Self Association

scholarly journals Stereoconfiguration of amino acids in peptides from a mycobacillin-synthesizing cell-free system (Short Communications)

1973 ◽  
Vol 131 (3) ◽  
pp. 623-624 ◽  
Author(s):  
S. Sengupta ◽  
S. K. Bose
Keyword(s):  
Amino Acids ◽  
Amino Acid ◽  
Glutamate Decarboxylase ◽  
Decarboxylase Activity ◽  
Acid Oxidase ◽  
Amino Acid Deprivation ◽  
Amino Acid Oxidase ◽  
Free System ◽  
Cell Free System

The stereoconfiguration of amino acids, as determined by treatment with L-amino acid oxidase, d-amino acid oxidase and l-glutamate decarboxylase (containing l-aspartate decarboxylase activity), in the peptides from a mycobacillin-synthesizing cell-free system is identical with that of the growing mycobacillin peptide chaid if its synthesis starts from l-proline and is interrupted at various points by amino acid deprivation.

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