mTORC1 signalling and mRNA translation

2009 ◽  
Vol 37 (1) ◽  
pp. 227-231 ◽  
Author(s):  
Christopher G. Proud
Keyword(s):  
Protein Synthesis ◽  
Growth Factors ◽  
Protein Kinases ◽  
Mammalian Target Of Rapamycin ◽  
Mrna Translation ◽  
Protein Accumulation ◽  
Anabolic Hormones ◽  
Cell Functions ◽  
Translation Factors ◽  
Specific Mrnas

Signalling through mTORC1 (mammalian target of rapamycin complex 1) is important in controlling many cell functions, including protein synthesis, which it activates. mTORC1 signalling is activated by stimuli which promote protein accumulation such as anabolic hormones, growth factors and hypertrophic stimuli. mTORC1 signalling regulates several components of the protein synthetic machinery, including initiation and elongation factors, protein kinases which phosphorylate the ribosome and/or translation factors, and the translation of specific mRNAs. However, there are still important gaps in our understanding of the actions of mTORC1 and the relative contributions that different targets of mTORC1 make to the activation of protein synthesis remain to be established.

Stable isotope-labelling analysis of the impact of inhibition of the mammalian target of rapamycin on protein synthesis

2012 ◽  
Vol 444 (1) ◽  
pp. 141-151 ◽  
Author(s):  
Yilin Huo ◽  
Valentina Iadevaia ◽  
Zhong Yao ◽  
Isabelle Kelly ◽  
Sabina Cosulich ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
Stable Isotope ◽  
Mammalian Target Of Rapamycin ◽  
Mrna Translation ◽  
Target Of Rapamycin ◽  
Stable Isotope Labelling ◽  
Isotope Labelling ◽  
Cell Functions ◽  
Specific Mrnas ◽  
The Impact

mTORC1 [mTOR (mammalian target of rapamycin) complex 1] regulates diverse cell functions. mTORC1 controls the phosphorylation of several proteins involved in mRNA translation and the translation of specific mRNAs, including those containing a 5′-TOP (5′-terminal oligopyrimidine). To date, most of the proteins encoded by known 5′-TOP mRNAs are proteins involved in mRNA translation, such as ribosomal proteins and elongation factors. Rapamycin inhibits some mTORC1 functions, whereas mTOR-KIs (mTOR kinase inhibitors) interfere with all of them. mTOR-KIs inhibit overall protein synthesis more strongly than rapamycin. To study the effects of rapamycin or mTOR-KIs on synthesis of specific proteins, we applied pSILAC [pulsed SILAC (stable isotope-labelling with amino acids in cell culture)]. Our results reveal, first, that mTOR-KIs and rapamycin differentially affect the synthesis of many proteins. Secondly, mTOR-KIs inhibit the synthesis of proteins encoded by 5′-TOP mRNAs much more strongly than rapamycin does, revealing that these mRNAs are controlled by rapamycin-insensitive outputs from mTOR. Thirdly, the synthesis of certain other proteins shows a similar pattern of inhibition. Some of them appear to be encoded by ‘novel’ 5′-TOP mRNAs; they include proteins which, like known 5′-TOP mRNA-encoded proteins, are involved in protein synthesis, whereas others are enzymes involved in intermediary or anabolic metabolism. These results indicate that mTOR signalling may promote diverse biosynthetic processes through the translational up-regulation of specific mRNAs. Lastly, a SILAC-based approach revealed that, although rapamycin and mTOR-KIs have little effect on general protein stability, they stabilize proteins encoded by 5′-TOP mRNAs.

Signalling to translation: how signal transduction pathways control the protein synthetic machinery

2007 ◽  
Vol 403 (2) ◽  
pp. 217-234 ◽  
Author(s):  
Christopher G. Proud
Keyword(s):  
Protein Synthesis ◽  
Protein Kinases ◽  
Mammalian Cells ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Mrna Translation ◽  
Signalling Pathways ◽  
Cancer Tissue ◽  
Energy Status ◽  
Specific Mrnas

Recent advances in our understanding of both the regulation of components of the translational machinery and the upstream signalling pathways that modulate them have provided important new insights into the mechanisms by which hormones, growth factors, nutrients and cellular energy status control protein synthesis in mammalian cells. The importance of proper control of mRNA translation is strikingly illustrated by the fact that defects in this process or its control are implicated in a number of disease states, such as cancer, tissue hypertrophy and neurodegeneration. Signalling pathways such as those involving mTOR (mammalian target of rapamycin) and mitogen-activated protein kinases modulate the phosphorylation of translation factors, the activities of the protein kinases that act upon them and the association of RNA-binding proteins with specific mRNAs. These effects contribute both to the overall control of protein synthesis (which is linked to cell growth) and to the modulation of the translation or stability of specific mRNAs. However, important questions remain about both the contributions of individual regulatory events to the control of general protein synthesis and the mechanisms by which the translation of specific mRNAs is controlled.

scholarly journals Molecular mechanisms for the control of translation by insulin

1997 ◽  
Vol 328 (2) ◽  
pp. 329-341 ◽  
Author(s):  
G. Christopher PROUD ◽  
M. Richard DENTON
Keyword(s):  
Ribosomal Protein ◽  
Molecular Mechanisms ◽  
Glycogen Synthase ◽  
Mrna Translation ◽  
Initiation Factor ◽  
Chain Elongation ◽  
S6 Kinase ◽  
Ribosomal Protein S6 ◽  
Translation Factors ◽  
Specific Mrnas

Insulin acutely stimulates protein synthesis in mammalian cells, and this involves activation of the process of mRNA translation. mRNA translation is a complex multi-step process mediated by proteins termed translation factors. Several translation factors are regulated in response to insulin, often as a consequence of changes in their states of phosphorylation. The initiation factor eIF4E binds to the cap structure at the 5ʹ-end of the mRNA and mediates assembly of an initiation-factor complex termed eIF4F. Assembly of this complex can be regulated by eIF4E-binding proteins (4E-BPs), which inhibit eIF4F complex assembly. Insulin induces phosphorylation of the 4E-BPs, resulting in alleviation of the inhibition. This regulatory mechanism is likely to be especially important for the control of the translation of specific mRNAs whose 5ʹ-untranslated regions (5ʹ-UTRs) are rich in secondary structure. Translation of another class of mRNAs, those with 5ʹ-UTRs containing polypyrimidine tracts is also activated by insulin and this, like phosphorylation of the 4E-BPs, appears to involve the rapamycin-sensitive signalling pathway which leads to activation of the 70 kDa ribosomal protein S6 kinase (p70 S6 kinase) and the phosphorylation of the ribosomal protein S6. Overall stimulation of translation may involve activation of initiation factor eIF2B, which is required for all initiation events. This effect is dependent upon phosphatidylinositol 3-kinase and may involve the inactivation of glycogen synthase kinase-3 and consequent dephosphorylation of eIF2B, leading to its activation. Peptide-chain elongation can also be activated by insulin, and this is associated with the dephosphorylation and activation of elongation factor eEF2, probably as a consequence of the insulin-induced reduction in eEF2 kinase activity. Thus multiple signalling pathways acting on different steps in translation are involved in the activation of this process by insulin and lead both to general activation of translation and to the selective regulation of specific mRNAs.

scholarly journals Activation of mRNA translation in rat cardiac myocytes by insulin involves multiple rapamycin-sensitive steps

2000 ◽  
Vol 278 (4) ◽  
pp. H1056-H1068 ◽  
Author(s):  
Lijun Wang ◽  
Xuemin Wang ◽  
Christopher G. Proud
Keyword(s):  
Protein Synthesis ◽  
Protein Kinase ◽  
Signaling Pathways ◽  
Glycogen Synthase ◽  
Mrna Translation ◽  
Mitogen Activated Protein Kinase ◽  
Initiation Factor ◽  
Translation Factors ◽  
P70 S6k ◽  
Eef2 Kinase

Insulin acutely activates protein synthesis in ventricular cardiomyocytes from adult rats. In this study, we have established the methodology for studying the regulation of the signaling pathways and translation factors that may be involved in this response and have examined the effects of acute insulin treatment on them. Insulin rapidly activated the 70-kDa ribosomal S6 kinase (p70 S6k), and this effect was inhibited both by rapamycin and by inhibitors of phosphatidylinositol 3-kinase. The activation of p70 S6k is mediated by a signaling pathway involving the mammalian target of rapamycin (mTOR), which also modulates other translation factors. These include the eukaryotic initiation factor (eIF) 4E binding proteins (4E-BPs) and eukaryotic elongation factor 2 (eEF2). Insulin caused phosphorylation of 4E-BP1 and induced its dissociation from eIF4E, and these effects were also blocked by rapamycin. Concomitant with this, insulin increased the binding of eIF4E to eIF4G. Insulin also activated protein kinase B (PKB), which may lie upstream of p70 S6k and 4E-BP1, with the activation of the different isoforms being in the order α>β>γ. Insulin also caused inhibition of glycogen synthase kinase 3, which lies downstream of PKB, and of eEF2 kinase. The phosphorylation of eEF2 itself was also decreased by insulin, and this effect and the inactivation of eEF2 kinase were attenuated by rapamycin. The activation of overall protein synthesis by insulin in cardiomyocytes was substantially inhibited by rapamycin (but not by inhibitors of other specific signaling pathways, e.g., mitogen-activated protein kinase), showing that signaling events linked to mTOR play a major role in the control of translation by insulin in this cell type.

scholarly journals Regulation of translation by one-carbon metabolism in bacteria and the eukaryotic organelles

2020 ◽  
pp. jbc.REV120.011985
Author(s):  
Sunil Shetty ◽  
Umesh Varshney
Keyword(s):  
Protein Synthesis ◽  
Translation Initiation ◽  
Carbon Metabolism ◽  
Mrna Translation ◽  
Energy Reserves ◽  
Cellular Activity ◽  
Translation Factors ◽  
Translation Apparatus ◽  
Alternative Translation ◽  
One Carbon Metabolism

Protein synthesis is an energetically costly cellular activity. It is therefore important that the process of mRNA translation remains in excellent synchrony with cellular metabolism and its energy reserves. Unregulated translation could lead to the production of incomplete, mistranslated, or misfolded proteins, squandering the energy needed for cellular sustenance, and causing cytotoxicity. One-carbon metabolism (OCM), an integral part of cellular intermediary metabolism, produces a number of one-carbon unit intermediates (formyl, methylene, methenyl, methyl). These OCM intermediates are required for the production of amino acids like methionine, and biomolecules such as purines, thymidylate, and redox regulators. In this review, we discuss how OCM impacts the translation apparatus (composed of ribosome, tRNA, mRNA, and translation factors) and regulates crucial steps in protein synthesis. More specifically, we address how the OCM metabolites regulate the fidelity and rate of translation initiation in bacteria and eukaryotic organelles such as mitochondria. Modulation of the fidelity of translation initiation by OCM opens new avenues to understand alternative translation mechanisms involved in stress tolerance and drug resistance.

scholarly journals Oncogenic kinases and perturbations in protein synthesis machinery and energetics in neoplasia

2019 ◽  
Vol 62 (2) ◽  
pp. R83-R103 ◽  
Author(s):  
Oro Uchenunu ◽  
Michael Pollak ◽  
Ivan Topisirovic ◽  
Laura Hulea
Keyword(s):  
Protein Synthesis ◽  
Energy Metabolism ◽  
Kinase Inhibitors ◽  
Mammalian Target Of Rapamycin ◽  
Mrna Translation ◽  
Cellular Energy ◽  
Cellular Energy Metabolism ◽  
Protein Synthesis Machinery ◽  
Energy Consuming ◽  
Translational Apparatus

Notwithstanding that metabolic perturbations and dysregulated protein synthesis are salient features of cancer, the mechanism underlying coordination of cellular energy balance with mRNA translation (which is the most energy consuming process in the cell) is poorly understood. In this review, we focus on recently emerging insights in the molecular underpinnings of the cross-talk between oncogenic kinases, translational apparatus and cellular energy metabolism. In particular, we focus on the central signaling nodes that regulate these processes (e.g. the mechanistic/mammalian target of rapamycin MTOR) and the potential implications of these findings on improving the anti-neoplastic efficacy of oncogenic kinase inhibitors.

scholarly journals O-GlcNAc Cycling Enzymes Associate with the Translational Machinery and Modify Core Ribosomal Proteins

2010 ◽  
Vol 21 (12) ◽  
pp. 1922-1936 ◽  
Author(s):  
Quira Zeidan ◽  
Zihao Wang ◽  
Antonio De Maio ◽  
Gerald W. Hart
Keyword(s):  
Protein Synthesis ◽  
Posttranslational Modifications ◽  
Ribosomal Proteins ◽  
Ribosome Biogenesis ◽  
Mammalian Target Of Rapamycin ◽  
Nuclear Staining ◽  
Mtor Signaling Pathway ◽  
Translational Machinery ◽  
Translation Factors ◽  
Nucleolar Stress

Protein synthesis is globally regulated through posttranslational modifications of initiation and elongation factors. Recent high-throughput studies have identified translation factors and ribosomal proteins (RPs) as substrates for the O-GlcNAc modification. Here we determine the extent and abundance of O-GlcNAcylated proteins in translational preparations. O-GlcNAc is present on many proteins that form active polysomes. We identify twenty O-GlcNAcylated core RPs, of which eight are newly reported. We map sites of O-GlcNAc modification on four RPs (L6, L29, L32, and L36). RPS6, a component of the mammalian target of rapamycin (mTOR) signaling pathway, follows different dynamics of O-GlcNAcylation than nutrient-induced phosphorylation. We also show that both O-GlcNAc cycling enzymes OGT and OGAse strongly associate with cytosolic ribosomes. Immunofluorescence experiments demonstrate that OGAse is present uniformly throughout the nucleus, whereas OGT is excluded from the nucleolus. Moreover, nucleolar stress only alters OGAse nuclear staining, but not OGT staining. Lastly, adenovirus-mediated overexpression of OGT, but not of OGAse or GFP control, causes an accumulation of 60S subunits and 80S monosomes. Our results not only establish that O-GlcNAcylation extensively modifies RPs, but also suggest that O-GlcNAc play important roles in regulating translation and ribosome biogenesis.

scholarly journals Vasohibin1, a new IRES trans-acting factor for induction of (lymph)angiogenic factors in early hypoxia

2018 ◽  
Author(s):  
Fransky Hantelys ◽  
Anne-Claire Godet ◽  
Florian David ◽  
Florence Tatin ◽  
Edith Renaud-Gabardos ◽  
...  
Keyword(s):  
Gene Expression ◽  
Protein Synthesis ◽  
Growth Factors ◽  
Ischemic Heart ◽  
Transcriptional Level ◽  
Angiogenic Growth Factors ◽  
Internal Ribosome Entry ◽  
Global Protein Synthesis ◽  
Specific Mrnas ◽  
Angiogenic Genes

ABSTRACTHypoxia, a major inducer of angiogenesis, is known to trigger major changes of gene expression at the transcriptional level. Furthermore, global protein synthesis is blocked while internal ribosome entry sites (IRES) allow specific mRNAs to be translated. Here we report the transcriptome and translatome signatures of (lymph)angiogenic genes in hypoxic HL-1 cardiomyocytes: most genes are not induced at the transcriptome-, but at the translatome level, including all IRES-containing mRNAs. Our data reveal activation of (lymph)angiogenic mRNA IRESs in early hypoxia. We identify vasohibin1 (VASH1) as an IRES trans-acting factor (ITAF) able to activate FGF1 and VEGFD IRESs in hypoxia while it inhibits several IRESs in normoxia. Thus this new ITAF may have opposite effects on IRES activities. These data suggest a generalized process of IRES-dependent translational induction of (lymph)angiogenic growth factors expression in early hypoxia, whose pathophysiological relevance is to trigger formation of new functional vessels in ischemic heart. VASH1 is not always required, indicating that the IRESome composition is variable, thus allowing subgroups of IRESs to be activated under the control of different ITAFs.

The mTOR Pathway in the Control of Protein Synthesis

Physiology ◽  
2006 ◽  
Vol 21 (5) ◽  
pp. 362-369 ◽  
Author(s):  
Xuemin Wang ◽  
Christopher G. Proud
Keyword(s):  
Amino Acids ◽  
Protein Synthesis ◽  
Growth Factors ◽  
Mammalian Target Of Rapamycin ◽  
Mtor Pathway ◽  
Target Of Rapamycin ◽  
Cell Physiology ◽  
Elongation Factors ◽  
Energy Deficiency

Signaling through mammalian target of rapamycin (mTOR) is activated by amino acids, insulin, and growth factors, and impaired by nutrient or energy deficiency. mTOR plays key roles in cell physiology. mTOR regulates numerous components involved in protein synthesis, including initiation and elongation factors, and the biogenesis of ribosomes themselves.

Dysregulation of Neuronal Protein Synthesis in Alzheimer’s Disease

2020 ◽  
Author(s):  
Tao Ma
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Protein Synthesis ◽  
Synaptic Plasticity ◽  
Mammalian Target Of Rapamycin ◽  
Mrna Translation ◽  
Synaptic Function ◽  
Initiation Factor ◽  
Early Event ◽  
Molecular Signaling

Currently there is no effective cure or intervention available for Alzheimer’s disease (AD), a devastating neurodegenerative disease and the most common form of dementia. It is urgent to understand the basic cellular/molecular signaling mechanisms underlying AD pathophysiology to identify novel therapeutic targets and diagnostic biomarkers. Many studies indicate impaired synaptic function as a key and early event in AD pathogenesis. Mounting evidence suggests that dysregulations in mRNA translation (protein synthesis) may contribute to the development of synaptic dysfunction and cognitive defects in neurodegenerative diseases including AD. Protein synthesis happens in three phases (initiation, elongation, and termination) and is tightly controlled through regulation of multiple signaling pathways in response to various stimuli. Integral protein synthesis is indispensable for memory formation and maintenance of synaptic plasticity. Interruption of protein synthesis homeostasis can lead to impairments in cognition and synaptic plasticity. This chapter reviews recent studies supporting the idea that impaired protein synthesis is an important mechanism underlying AD-associated cognitive deficits and synaptic failure. It focuses on three signaling cascades controlling protein synthesis: eukaryotic initiation factor 2α (eIF2α), the mammalian target of rapamycin complex 1 (mTORC1), and eukaryotic elongation factor 2 (eEF2). Findings from human and animal studies demonstrating an association between dysregulation of these pathways and AD pathophysiology are summarized and discussed.

Sign in / Sign up

Export Citation Format

Share Document