Eukaryotic initiation factor 2B (eIF2B)

Webb, Benjamin L. J.; Proud, Christopher G.

doi:10.1016/s1357-2725(97)00039-3

Cited by 83 publications

(63 citation statements)

References 11 publications

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“…A growing body of evidence has suggested a link between the regulation of protein synthesis, growth control and neoplastic transformation. 25 Events required for the protein synthesis initiation are generally regarded as the rate-limiting steps, with particular attention being paid to the availability and function of the smallest a subunit of eIF2, 26 the guanine nucleotide exchange factor eIF2B 27 and the cap-binding factor eIF4E. 28 eIF2B is a heteropentameric protein, which catalyses a key step in translation initiation, that is the exchange of guanine nucleotides on initiation factor eIF2.…”

Section: Discussionmentioning

confidence: 99%

“…28 eIF2B is a heteropentameric protein, which catalyses a key step in translation initiation, that is the exchange of guanine nucleotides on initiation factor eIF2. 27 In addition, phosphorylation of the a subunit of eIF2 plays a crucial role in protein synthesis control. 29 When eIF2a is phosphorylated, eIF2-GDP binds irreversibly to eIF2B and blocks GDP/GTP recycling and translation initiation is inhibited.…”

Section: Discussionmentioning

confidence: 99%

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RETRACTED ARTICLE: Oncolysis of pancreatic tumour cells by a γ34.5-deleted HSV-1 does not rely upon Ras-activation, but on the PI 3-kinase pathway

et al. 2006

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The ability of viruses to selectively target, replicate within, and destroy tumour cells without deleterious effects in normal cells (oncolysis), makes the use of viruses as an attractive tool for cancer treatment. Pancreatic adenocarcinoma, being insensitive to traditional therapy and having a rather poor prognosis, represents a suitable target to evaluate viral oncolysis as a novel therapeutic approach. Herpes simplex virus (HSV) has been reported to produce an oncolytic effect in cells overexpressing Ras. As Ras signalling is frequently aberrant in pancreatic cancer, we compared four pancreatic cell lines (which differ in the presence of mutated or wild-type ras) for their ability to support growth of g34.5-replication attenuated HSV-1 (R3616). Our data show that permissiveness to viral replication is neither associated with enhanced Ras signalling nor with defective PKR activity. By contrast, we provide evidence that disregulation of the PI 3-kinase signalling pathway allows conditionally replication-defective R3616 virus to overcome the cellular antiviral activity.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

RETRACTED ARTICLE: Oncolysis of pancreatic tumour cells by a γ34.5-deleted HSV-1 does not rely upon Ras-activation, but on the PI 3-kinase pathway

et al. 2006

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“…During recognition of the AUG start codon, the GTP bound to eIF2 is hydrolyzed, and the eIF2•GDP binary complex is subsequently released from the ribosome (Algire et al, 2005). In order for eIF2 to participate in successive rounds of initiation, the GDP bound to eIF2 must be exchanged for GTP, a process catalyzed by the guanine nucleotide exchange factor (GEF) eIF2B (Price andProud, 1994, Webb andProud, 1997). At normal cellular concentrations of magnesium, the dissociation constant for GDP is approximately 400-fold lower than for GTP (Panniers et al, 1988), therefore the exchange of eIF2-bound GDP for GTP by eIF2B activity is an absolute requirement for sustained mRNA translation and protein synthesis.…”

Section: Introductionmentioning

confidence: 99%

“…Deletion of each of these gene products, with the exception of the α-subunit, is lethal in yeast (Hinnebusch, 1996), highlighting the importance of eIF2B activity for maintenance of cellular homeostasis. eIF2B activity is regulated via diverse mechanisms including, 1) phosphorylation of the α-subunit of (eIF2α) on Ser-51, 2) phosphorylation of eIF2Bε, 3) the redox state of pyridine dinucleotides, and 4) the abundance of eIF2B relative to its substrate eIF2 (reviewed in Webb and Proud, 1997).…”

Section: Introductionmentioning

confidence: 99%

Activation of the mammalian target of rapamycin complex 1 is both necessary and sufficient to stimulate eukaryotic initiation factor 2Bɛ mRNA translation and protein synthesis

Kubica

Crispino

Gallagher

et al. 2008

The International Journal of Biochemistry & Cell Biology

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In a previous study we demonstrated a requirement for activation of mTORC1 in the stimulation of eIF2Bε mRNA translation in skeletal muscle in response to resistance exercise. Although that study established the necessity of mTORC1 activation, the experimental model used did not lend itself readily to address the question of whether or not mTORC1 activation was sufficient to produce the response. Therefore, the present study was designed to address the sufficiency of mTORC1 activation, using cultures of Rat2 fibroblasts in which mTORC1 signaling was repressed by serum/ leucine-depletion and stimulated by repletion of leucine and/or IGF-1. Repletion with leucine and IGF-1 caused a shift of eIF2Bε mRNA into actively translating polysomes and a stimulation of new eIF2Bε protein synthesis, but had no effect on mRNAs encoding the other four eIF2B subunits. Stimulation of eIF2Bε translation was reversed by pre-treatment with the mTORC1 inhibitor rapamycin. Exogenous overexpression of FLAG-Rheb, a proximal activator of mTORC1, also caused a re-distribution of eIF2Bε mRNA into polysomes and a stimulation of eIF2Bε protein synthesis. The stimulation of eIF2Bε mRNA translation occurred in the absence of any effect on eIF2Bε mRNA abundance. RNAi-mediated knockdown of eIF2Bε resulted in reduced cellular proliferation, a result that phenocopied the known cytostatic effect of mTORC1 repression. Overall the results demonstrate that activation of mTORC1 is both necessary and sufficient to stimulate eIF2Bε mRNA translation and that this response may represent a novel mechanism through which mTORC1 can affect mRNA translation initiation, rates of protein synthesis, and cellular growth/ proliferation.

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“…The binding of the Met-tRNA i to the 40 S ribosomal subunit is dependent on the formation of the translational ternary complex that assembles only when eIF2 is in its GTP-bound state (21,22). The 40 S ribosomal subunit, in association with a number of initiation factors (including the eIF4F complex), delivers the eIF2-GTP-bound Met-tRNAi to the AUG start codon.…”

mentioning

confidence: 99%

Glucose-stimulated Protein Synthesis in Pancreatic β-Cells Parallels an Increase in the Availability of the Translational Ternary Complex (eIF2-GTP·Met-tRNAi) and the Dephosphorylation of eIF2α

Gomez¹,

Powell²,

Greenman³

et al. 2004

Journal of Biological Chemistry

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In pancreatic ␤-cells, glucose causes a rapid increase in the rate of protein synthesis. However, the mechanism by which this occurs is poorly understood. In this report, we demonstrate, in the pancreatic ␤-cell line MIN6, that glucose stimulates the recruitment of ribosomes onto the mRNA, indicative of an increase in the rate of the initiation step of protein synthesis. This increase in the rate of initiation is not mediated through an increase in the availability of the initiation complex eIF4F, because glucose is unable to stimulate eIF4F assembly or, in the absence of amino acids, modulate the phosphorylation status of 4E-BP1. Moreover, in MIN6 cells and isolated islets of Langerhans, rapamycin, an inhibitor of the mammalian target of rapamycin, only partially inhibited glucose-stimulated protein synthesis. However, we show that glucose stimulates the dephosphorylation of eIF2␣ in MIN6 cells and the assembly of the translational ternary complex, eIF2-GTP⅐Met-tRNAi, in both MIN6 cells and islets of Langerhans. The changes in the phosphorylation of eIF2␣ are not mediated by the PKR-like endoplasmic reticulum eIF2␣ kinase (PERK), because PERK is not phosphorylated at low glucose concentrations and overexpression of a dominant negative form of PERK has no significant effect on either glucose-stimulated protein synthesis or the phosphorylation of eIF2␣. Taken together, these results indicate that glucose-stimulated protein synthesis in pancreatic ␤-cells is regulated by a mechanism largely independent of the activity of mammalian target of rapamycin, but which is likely to be dependent on the availability of the translational ternary complex, regulated by the phosphorylation status of eIF2␣.

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Eukaryotic initiation factor 2B (eIF2B)

Cited by 83 publications

References 11 publications

RETRACTED ARTICLE: Oncolysis of pancreatic tumour cells by a γ34.5-deleted HSV-1 does not rely upon Ras-activation, but on the PI 3-kinase pathway

RETRACTED ARTICLE: Oncolysis of pancreatic tumour cells by a γ34.5-deleted HSV-1 does not rely upon Ras-activation, but on the PI 3-kinase pathway

Activation of the mammalian target of rapamycin complex 1 is both necessary and sufficient to stimulate eukaryotic initiation factor 2Bɛ mRNA translation and protein synthesis

Glucose-stimulated Protein Synthesis in Pancreatic β-Cells Parallels an Increase in the Availability of the Translational Ternary Complex (eIF2-GTP·Met-tRNAi) and the Dephosphorylation of eIF2α

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