Disease relevance of Eif4e

• Finally, treatment of myotubes with PD-98059 or dnMEK1 adenovirus before TNF + INS addition resulted in a derepression of protein synthesis and the association of eIF4G with eIF4E [1].
• We identified mRNA subsets from P19 embryonal carcinoma stem cells by using mRNA-binding proteins HuB, eIF-4E, and PABP that are known to play a role in translation [2].
• Our data provides evidence that JNK2alpha2 is the major active JNK isoform and is involved in the promotion of proliferation and growth of human glioblastoma tumors through specific activation of AKT and overexpression of eIF4E [3].
• The eukaryotic translation initiation factor 4E is not modified during the course of vaccinia virus replication [4].
• A CHO cell line expressing high levels of eIF4E (rb4E) was developed by infecting cells with retroviruses containing a full-length mouse cDNA for eIF4E [5].

High impact information on Eif4e

• The translation factor eIF-4E promotes tumor formation and cooperates with c-Myc in lymphomagenesis [6].
• Our results implicate activation of eIF-4E as a key event in oncogenic transformation by phosphoinositide-3 kinase and Akt [6].
• We have shown previously that overexpression of eIF-4E in rodent fibroblasts results in tumorigenic transformation. eIF-4E also exhibits mitogenic activity when microinjected into serum-starved NIH-3T3 cells [7].
• This inhibition is causally related to the dephosphorylation and consequent activation of 4E-BP1, a protein recently identified as a repressor of the cap-binding protein, eIF-4E, function [8].
• This effect may represent one mechanism by which eIF-4E regulates cell growth and transforms cells in culture [9].

Biological context of Eif4e

• We detected highly significant marker associations for acceptance on chromosome 12 (Eif4e), for preference on chromosome 1 (D1Rti2) and chromosome 7 (D7Mit7), and for HDS on chromosome 7 (Mpmv1) [10].
• These results strongly suggest that eIF4E phosphorylation at Ser209 is not essential for cell growth during development [11].
• Eukaryotic translation initiation factor 4E (eIF4E) is the mRNA 5' cap binding protein, which plays an important role in the control of translation [12].
• Translational homeostasis: eukaryotic translation initiation factor 4E control of 4E-binding protein 1 and p70 S6 kinase activities [12].
• Overall, the data are consistent with exercise-induced repression of mTOR signalling and global rates of mRNA translation, accompanied perhaps by up-regulated translation of selected mRNAs through regulatory mechanisms such as eIF4E and rpS6 phosphorylation, mediated by activation of the ERK1/2 pathway [13].

Anatomical context of Eif4e

• However, neither general protein synthesis nor cap-dependent translation, as assayed by a bicistronic reporter assay system, was affected in Mnk-deficient embryonic fibroblasts, despite the absence of phosphorylated eIF4E [11].
• Insulin and IGF-I increased the amount of eIF4G associated with eIF4E in nutrient-deprived C2C12 myotubes [14].
• Overexpression of eIF4E rendered polysome recruitment of mRNAs with structured 5' untranslated regions largely independent of growth factor and resistant to the PI3K inhibitor LY294002 [15].
• Overexpression of eIF4E did not induce factor-independent growth but specifically impaired differentiation into mature erythrocytes [15].
• Here we show that either serum treatment or activation of the stress-activated protein kinase (JNK/SAPK) led to enhanced phosphorylation of eIF4E in quiescent NIH 3T3 cells [16].

Associations of Eif4e with chemical compounds

• In Mnk1-Mnk2 DKO mice, no phosphorylated eIF4E was detected in any tissue studied, even after LPS or insulin injection [11].
• Removal of tetracycline induced eIF4E expression up to fivefold over endogenous levels [12].
• The association constant values of recombinant eIF4E for 20 different cap analogues cover six orders of magnitude; with the highest affinity observed for m(7)GTP (approximately 1.1 x 10(8) M(-1)) [17].
• In addition, overexpression of eIF4E rendered progenitors insensitive to the differentiation-inducing effect of LY294002, indicating that control of mRNA translation is a major pathway downstream of PI3K in the regulation of progenitor expansion [15].
• The amount of serine 1108-phosphorylated eIF4G (but not Ser209-phosphorylated eIF4E) was induced following PH [18].

Physical interactions of Eif4e

• Enhancement of the eIF4E affinity for cap occurs after binding to eIF4G peptides [17].
• Phosphorylation of 4E-BP1 at Ser65 and Thr70 is insufficient to prevent binding to eIF4E [17].
• 4E-binding protein 1 (BP1) and 4E-BP2 are small proteins that bind to eIF4E and inhibit translation [19].

Enzymatic interactions of Eif4e

• Strikingly, upon induction of eIF4E, 4E-BP1 became dephosphorylated and the extent of dephosphorylation was proportional to the expression level of eIF4E [12].

Regulatory relationships of Eif4e

• Insulin also increased the phosphorylation of PHAS-I and promoted dissociation of the PHAS-I eukaryotic initiation factor-4E (eIF-4E) complex, effects that were maximal within 10 min [20].
• It has been proposed that binding of the eukaryotic translation initiation factor 4E (eIF-4E) to the inhibitory protein 4BP-1 blocks translation by preventing access of eIF-4G to the 5' cap of the mRNA [21].
• The eukaryotic initiation factor 4E (eIF4E) is a key regulator of protein translation whose function is activated by the Akt and Ras proto-oncogenic signal transduction pathways. eIF4E enhances the translation of mRNAs encoding several genes involved in tumorigenesis and acts as a proto-oncogene, in vitro, when overexpressed in immortalized cells [22].
• Eukaryotic translation initiation factor 4E regulates expression of cyclin D1 at transcriptional and post-transcriptional levels [23].
• Erythropoietin stimulated phosphorylation of eIF-4E in FVA cells within 30 minutes, and this effect was maximal at 60 minutes [24].

Other interactions of Eif4e

• In contrast, the phosphorylation of Akt, an upstream effector of both p70(S6k) and 4E-BP phosphorylation, was not affected by eIF4E induction [12].
• Biophysical studies of eIF4E cap-binding protein: recognition of mRNA 5' cap structure and synthetic fragments of eIF4G and 4E-BP1 proteins [17].
• The interaction between eIF4E and eIF4E-binding protein 1 (4E-BP1), however, was not inhibited by aptamer 1 [25].
• Expression of eIF-4E and eIF-2 alpha correlated with c-myc expression in fibroblasts after growth stimulation [26].
• In previous studies these translation initiation factors could induce neoplastic growth because overexpression of eIF-4E-transformed cells and inhibition of a suppressor of eIF-2 alpha (eIF-2 alpha kinase) also caused malignant transformation [26].

Analytical, diagnostic and therapeutic context of Eif4e

• Fluorescence spectroscopy and high-sensitivity isothermal titration calorimetry were used to examine the thermodynamics of eIF4E binding to a cap-analogue, 7-methylGpppG [27].
• A sequence alignment shows that LeishIF4E-1 lacks the region that parallels the C terminus in the murine eIF4E [28].
• METHODS: The cDNA of mouse eukaryotic translation initiation factor 4E coding region (either wild-type or mutant, where Trp-56 was mutated to Ala) was transfected into MAC-T cells, and its protein expression was detected by Western blot analysis [29].
• Immunodetection of phosphorylated and unphosphorylated eIF-4E in cell lysates fractionated by two-dimensional gel electrophoresis showed that the steady-state levels of phosphorylated and unphosphorylated forms of eIF-4E were similar in uninfected and virus-infected cells [4].
• Analyses of eIF-4E that was metabolically labeled with [32P] and then purified by affinity chromatography using m7GTP-Sepharose 4B, indicated that neither the incorporation of radiolabel into eIF-4E nor the amounts of eIF-4E capable of binding to cap structures changed significantly during virus replication [4].

References