Eukaryotic Initiation Factors (eIF) 2α and 4E Expression, Localization, and Phosphorylation in Brain Tumors

Tejada, Sonia; Lobo, M.V. Toledo; García-Villanueva, Mercedes; Sacristán, Silvia; Pérez-Morgado, M. Isabel; Salinas, Matilde; Martı́n, M. Elena

doi:10.1369/jhc.2009.952929

Cited by 31 publications

(18 citation statements)

References 47 publications

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“…A sustained increase in phosphorylated eIF2␣ can cause C/EBP homologous protein (CHOP) mediated apoptosis (Harding et al, 2000;Scheuner et al, 2001;Galehdar et al, 2010). Previous reports described eIF2␣ in the nucleus, which may function to regulate transcriptional and translational processes (Goldstein et al, 1999;DuRose et al, 2009;Tejada et al, 2009). We found that nicotine exposure significantly inhibited nuclear eIF2␣ phosphorylation in ␣4␤2-overexpressing neurons, without affecting total eIF2␣ expression (Fig.…”

Section: Discussionmentioning

confidence: 55%

Pharmacological Chaperoning of Nicotinic Acetylcholine Receptors Reduces the Endoplasmic Reticulum Stress Response

Srinivasan

Richards²,

Xia³

et al. 2012

Mol Pharmacol

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We report the first observation that endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) can decrease when a central nervous system drug acts as an intracellular pharmacological chaperone for its classic receptor. Transient expression of ␣4␤2 nicotinic receptors (nAChRs) in Neuro-2a cells induced the nuclear translocation of activating transcription factor 6 (ATF6), which is part of the UPR. Cells were exposed for 48 h to the full agonist nicotine, the partial agonist cytisine, or the competitive antagonist dihydro-␤-erythroidine; we also tested mutant nAChRs that readily exit the ER. Each of these four manipulations increased Sec24D-enhanced green fluorescent protein fluorescence of condensed ER exit sites and attenuated translocation of ATF6-enhanced green fluorescent protein to the nucleus. However, we found no correlation among the manipulations regarding other tested parameters [i.e., changes in nAChR stoichiometry (␣4 2 ␤2 3 versus ␣4 3 ␤2 2 ), changes in ER and trans-Golgi structures, or the degree of nAChR up-regulation at the plasma membrane]. The four manipulations activated 0 to 0.4% of nAChRs, which shows that activation of the nAChR channel did not underlie the reduced ER stress. Nicotine also attenuated endogenously expressed ATF6 translocation and phosphorylation of eukaryotic initiation factor 2␣ in mouse cortical neurons transfected with ␣4␤2 nAChRs. We conclude that, when nicotine accelerates ER export of ␣4␤2 nAChRs, this suppresses ER stress and the UPR. Suppression of a sustained UPR may explain the apparent neuroprotective effect that causes the inverse correlation between a person's history of tobacco use and susceptibility to developing Parkinson's disease. This suggests a novel mechanism for neuroprotection by nicotine.

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Section: Discussionmentioning

confidence: 55%

Pharmacological Chaperoning of Nicotinic Acetylcholine Receptors Reduces the Endoplasmic Reticulum Stress Response

Srinivasan

Richards²,

Xia³

et al. 2012

Mol Pharmacol

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“…Activation of AKT promotes protein translation initiation, which is dependent upon expression and assembly of several eIF complexes (Jackson et al, 2010; Silvera et al, 2010). Intriguingly, high levels of eIF4E correlate with meningioma grade (Tejada et al, 2009). Meningiomas lacking NF2 frequently have more abundant eIF3C than NF2 -expressing tumors (Scoles et al, 2006).…”

Section: Discussionmentioning

confidence: 99%

Overexpression of eIF4F components in meningiomas and suppression of meningioma cell growth by inhibiting translation initiation

Oblinger

Burns

Huang

et al. 2018

Experimental Neurology

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Meningiomas frequently display activation of the PI3K/AKT/mTOR pathway, leading to elevated levels of phospho-4E binding proteins, which enhances protein synthesis; however, it is not known whether inhibition of protein translation is an effective treatment option for meningiomas. We found that human meningiomas expressed high levels of the three components of the eukaryotic initiation factor 4F (eIF4F) translation initiation complex, eIF4A, eIF4E, and eIF4G. The expression of eIF4A and eIF4E was important in sustaining the growth of NF2-deficient benign meningioma Ben-Men-1 cells, as shRNA-mediated knockdown of these proteins strongly reduced cell proliferation. Among a series of 23 natural compounds evaluated, silvestrol, which inhibits eIF4A, was identified as being the most growth inhibitory in both primary meningioma and Ben-Men-1 cells. Silvestrol treatment of meningioma cells prominently induced G2/M arrest. Consistently, silvestrol significantly decreased the amounts of cyclins D1, E1, A, and B, PCNA and Aurora A. In addition, total and phosphorylated AKT, ERK and FAK, which have been shown to be important drivers for meningioma cell proliferation, were markedly lower in silvestrol-treated Ben-Men-1 cells. Our findings suggest that inhibiting protein translation could be a potential treatment for meningiomas.

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“…It was also noted that the effect of eIF3c and eIF3b on the cell cycle process is similar in tumour cells, as depletion of either eIF3c or eIF3b leads to cell cycle arrest at the G 0 /G 1 phase. It has previously been reported that cell cycle arrest caused by eIF3b depletion may be due to the suppression of cyclin expression, the elevation of p27Kip1 levels and the hypophosphorylation of Rb proteins (23). In consideration of the similarity between eIF3b and eIF3c, it is possible that eIF3c depletion induces cell cycle arrest through similar mechanisms.…”

Section: A B Cmentioning

confidence: 99%

Eukaryotic translation initiation factor 3, subunit C is overexpressed and promotes cell proliferation in human glioma U-87 MG cells

2015

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Abstract. Disrupted protein translation is prevalent in tumours. Eukaryotic translation initiation factors (eIFs) were found to play an important role in various tumours. However, the involvement of eIFs in glioma remains to be elucidated. The present study explored the expression and the role of eIF 3, subunit C (eIF3c) in human glioma. The expression of eIF3c in glioma tissues was evaluated by immunohistochemistry. The impact of eIF3c inhibition on U-87 MG was explored in vitro and in vivo by lentivirus-mediated siRNA targeting eIF3c. The results revealed that overexpression of eIF3c was present in glioma tissues. Knockdown of eIF3c significantly impaired cell proliferation and colony formation, further induced cell cycle arrest and apoptosis in the U-87 MG cell line. Furthermore, tumoursphere formation in the U-87 MG glioma xenograft model was blocked by eIF3c knockdown. The involvement of eIF3c in the tumorigenesis of glioma was confirmed, suggesting eIF3c may be a promising therapy target in human glioma.

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Eukaryotic Initiation Factors (eIF) 2α and 4E Expression, Localization, and Phosphorylation in Brain Tumors

Cited by 31 publications

References 47 publications

Pharmacological Chaperoning of Nicotinic Acetylcholine Receptors Reduces the Endoplasmic Reticulum Stress Response

Pharmacological Chaperoning of Nicotinic Acetylcholine Receptors Reduces the Endoplasmic Reticulum Stress Response

Overexpression of eIF4F components in meningiomas and suppression of meningioma cell growth by inhibiting translation initiation

Eukaryotic translation initiation factor 3, subunit C is overexpressed and promotes cell proliferation in human glioma U-87 MG cells

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