Glutamate-Dependent Phosphorylation of Elongation Factor-2 and Inhibition of Protein Synthesis in Neurons

Marin, Philippe; Nastiuk, Kent L.; Daniel, Nadine; Girault, Jean‐Antoine; Czernik, Andrew J.; Głowiński, J.; Nairn, Angus C.; Prémont, Joël

doi:10.1523/jneurosci.17-10-03445.1997

Cited by 163 publications

(179 citation statements)

References 45 publications

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“…Equal amounts of protein were subjected to SDS-PAGE using Criterion Precast 10-20% Tris ⅐ HCl gradient gels (Bio-Rad Laboratories) followed by transfer of proteins to PVDF membranes as described previously (53). After blocking with nonfat dry milk, the membranes were incubated with antibodies specific for eEF-1A (Santa Cruz Antibodies, Santa Cruz, CA) or eEF-2 (35,53). The phosphorylation status of eEF-2 in the tissue homogenate was analyzed by sequential immunoblotting first with an antibody that specifically recognized eEF-2 phosphorylated on Thr 56 (35).…”

Section: Methodsmentioning

confidence: 99%

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TNF-α impairs heart and skeletal muscle protein synthesis by altering translation initiation

Lang

Frost

Nairn

et al. 2002

American Journal of Physiology-Endocrinology and Metabolism

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This study examined potential mechanisms contributing to the inhibition of protein synthesis in skeletal muscle and heart after administration of tumor necrosis factor (TNF)-α. Rats had vascular catheters implanted, and TNF-α was infused continuously for 24 h. TNF-α decreased in vivo-determined rates of global protein synthesis in gastrocnemius (39%) and heart (25%). The TNF-α-induced decrease in protein synthesis in the gastrocnemius involved a reduction in the synthesis of both myofibrillar and sarcoplasmic proteins. To identify potential mechanisms responsible for regulating mRNA translation, we examined several eukaryotic initiation factors (eIFs) and elongation factors (eEFs). TNF-α decreased the activity of eIF-2B in muscle (39%) but not in heart. This diminished activity was not caused by a reduction in the content of eIF-2Bε or the content and phosphorylation state of eIF-2α. Skeletal muscle and heart from TNF-α-treated rats demonstrated 1) an increased binding of the translation repressor 4E-binding protein-1 (4E-BP1) with eIF-4E, 2) a decreased amount of eIF-4E associated with eIF-4G, and 3) a decreased content of the hyperphosphorylated γ-form of 4E-BP1. In contrast, the infusion of TNF-α did not alter the content of eEF-1α or eEF-2, or the phosphorylation state of eEF-2. In summary, these data suggest that TNF-α impairs skeletal muscle and heart protein synthesis, at least in part, by decreasing mRNA translational efficiency resulting from an impairment in translation initiation associated with alterations in eIF-4E availability.

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Section: Methodsmentioning

confidence: 99%

“…eEF-2 is also important for normal mRNA translation and catalyzes the translocation of the peptidyl-tRNA from the A-site to the P-site on the ribosome. Alterations in the amount and/or phosphorylation state of eEF-1 and eEF-2 have been linked to changes in protein synthesis (35,53).…”

mentioning

confidence: 99%

TNF-α impairs heart and skeletal muscle protein synthesis by altering translation initiation

Lang

Frost

Nairn

et al. 2002

American Journal of Physiology-Endocrinology and Metabolism

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231

229

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“…This alteration in eEF2 phosphorylation at Thr56 is typically associated with a reduction in the interaction of the elongation factor with ribosomes, thereby decreasing global protein synthesis (Nairn and Palfrey, 1987;Ryazanov et al, 1991Ryazanov et al, , 1988, but an increase in the translation of some dendritic mRNAs (e.g. aCaMKII and Arc) has also been reported (Belelovsky et al, 2005;Chotiner et al, 2003;Marin et al, 1997;Park et al, 2008;Scheetz et al, 2000). However, in contrast with the results obtained following injection of BDNF in the dentate gyrus, the neurotrophin was without effect on eEF2 phosphorylation in synaptoneurosomes isolated from the same region, suggesting that the arresting of elongation may be limited to non-synaptic sites.…”

Section: Bdnf and Regulation Of Translation Machinerymentioning

confidence: 96%

BDNF-induced local protein synthesis and synaptic plasticity

2014

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a b s t r a c tBrain-derived neurotrophic factor (BDNF) is an important regulator of synaptic transmission and longterm potentiation (LTP) in the hippocampus and in other brain regions, playing a role in the formation of certain forms of memory. The effects of BDNF in LTP are mediated by TrkB (tropomyosin-related kinase B) receptors, which are known to be coupled to the activation of the Ras/ERK, phosphatidylinositol 3-kinase/Akt and phospholipase C-g (PLC-g) pathways. The role of BDNF in LTP is best studied in the hippocampus, where the neurotrophin acts at pre-and post-synaptic levels. Recent studies have shown that BDNF regulates the transport of mRNAs along dendrites and their translation at the synapse, by modulating the initiation and elongation phases of protein synthesis, and by acting on specific miRNAs. Furthermore, the effect of BDNF on transcription regulation may further contribute to long-term changes in the synaptic proteome. In this review we discuss the recent progress in understanding the mechanisms contributing to the short-and long-term regulation of the synaptic proteome by BDNF, and the role in synaptic plasticity, which is likely to influence learning and memory formation.This article is part of the Special Issue entitled 'BDNF Regulation of Synaptic Structure, Function, and Plasticity'.

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“…Mnk1, a kinase activated by Erk1/2 and p38 (19), phosphorylates eIF4E. Cellular stresses such as excitotoxicity or hydrogen peroxide in neurons (12,20,21), oxygen and glucose deprivation (22), and serum deprivation (23) in PC12 cells down-regulate protein synthesis. On the other hand, growth factors and neurotrophins enhance translation in cultured neurons, but different agents regulate specific translation factors through activation of Akt and/or Erk1/2 signaling pathways (24 -26).…”

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confidence: 99%

“…Likewise, persistent blockade of protein synthesis is associated with brain damage (10), and neuronal survival after focal ischemia may depend on the recovery of protein synthesis (11). Intracellular Ca 2ϩ overload by activation of glutamate receptors (12) or disturbances of endoplasmic reticulum Ca 2ϩ homeostasis decrease protein synthesis (13)(14)(15)(16). Protein synthesis is mainly regulated at the initiation step.…”

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confidence: 99%

Transforming Growth Factor-α Attenuates N-Methyl-D-aspartic Acid Toxicity in Cortical Cultures by Preventing Protein Synthesis Inhibition through an Erk1/2-dependent Mechanism

Petegnief

Friguls

Sanfeliu

et al. 2003

Journal of Biological Chemistry

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Transforming growth factor-␣ (TGF-␣), a ligand of the epidermal growth factor receptor, reduces the infarct size after focal cerebral ischemia in rat, but the molecular basis underlying the protection is unknown. Excitotoxicity and global inhibition of translation are acknowledged to contribute significantly to the ischemic damage. Here we studied whether TGF-␣ can rescue neurons from excitotoxicity in vitro and how it affects calcium homeostasis, protein synthesis, and the associated Akt and extracellular signal-regulated kinase 1/2 (Erk1/2) intracellular signaling pathways in mixed neuron-glia cortical cultures. We found that 100 ng/ml TGF-␣ attenuated neuronal cell death induced by a 30-min exposure to 35 M N-methyl-D-aspartic acid (NMDA) (as it reduced lactate dehydrogenase release, propidium iodide staining, and caspase-3 activation) and decreased the elevation of intracellular Ca 2؉ elicited by NMDA. TGF-␣ induced a prompt and sustained phosphorylation of Erk1/2 and prevented the loss of Akt-P induced by NMDA 3 h after exposure. The protective effect of TGF-␣ was completely prevented by PD 98059, an inhibitor of the Erk1/2 pathway. Studies of incorporation of [ 3 H]leucine into proteins showed that NMDA decreased the rate of protein synthesis, and TGF-␣ attenuated this effect. TGF-␣ stimulated the phosphorylation of the eukaryotic initiation factor 4E (eIF4E) but did not affect eIF2␣, two proteins involved in translation regulation. PD 98059 abrogated the TGF-␣ effect on eIF4E. Our data demonstrate that TGF-␣ exerts a neuroprotective action against NMDA toxicity, in which Erk1/2 activation plays a key role, and suggest that the underlying mechanisms involve recovery of translation inhibition, mediated at least in part by eIF4E phosphorylation.TGF-␣ 1 is protective in models of permanent and transient focal ischemia induced by occlusion of the middle cerebral artery in the rat (1, 2). Although TGF-␣ is known to promote neuronal survival (3) and to induce proliferation and differentiation of astrocytes in vitro (4), little is known about its effects on neural cells. TGF-␣ binds to the epidermal growth factor receptor (EGFR), which stimulation induces its dimerization, autophosphorylation on tyrosine residues, and triggers a cascade of reactions that requires the contribution of adapter proteins and kinases. EGFR activates several signal transduction pathways, among others are phosphatidylinositol 3-kinase/protein kinase B (PI 3-kinase/Akt) and the p44/p42 mitogen-activated protein kinase, also referred to as extracellular signal-regulated kinases 1/2 (Erk1/2) (5).Among the very early consequences of energy depletion after an ischemic insult to the brain are membrane depolarization that induces excitatory amino acid release and inhibition of global protein synthesis, and both significantly contribute to the development of brain infarct (6 -8). Indeed, glutamate receptor overactivation results in an increase in intracellular calcium and extensive neuronal death by excitotoxicity (9). Likewise, persistent block...

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Glutamate-Dependent Phosphorylation of Elongation Factor-2 and Inhibition of Protein Synthesis in Neurons

Cited by 163 publications

References 45 publications

TNF-α impairs heart and skeletal muscle protein synthesis by altering translation initiation

TNF-α impairs heart and skeletal muscle protein synthesis by altering translation initiation

BDNF-induced local protein synthesis and synaptic plasticity

Transforming Growth Factor-α Attenuates N-Methyl-D-aspartic Acid Toxicity in Cortical Cultures by Preventing Protein Synthesis Inhibition through an Erk1/2-dependent Mechanism

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