Disease relevance of Eif4e

• Oxidant stress stimulates phosphorylation of eIF4E without an effect on global protein synthesis in smooth muscle cells. Lack of evidence for a role of H202 in angiotensin II-induced hypertrophy [1].
• We have previously shown that sepsis decreases the phosphorylation of eIF4E [2].
• Phosphorylation of eIF2alpha and eIF4E and the association of eIF4E with 4E-BP1 were also greater than control values after ischemia but only in hearts perfused with glucose plus palmitate [3].
• Although hypoxia might be signalling via the rapamycin-sensitive pathway by changing eIF-4E availability, such a pathway is unlikely to be responsible for the depression in overall protein synthesis under hypoxia [4].
• The decrease in the levels of phosphorylated initiation factor 4E (eIF-4E) after 30-minute ischemia (from 32% to 16%) could explain, at least partially, the impairment of initiation during transient cerebral ischemia [5].

Psychiatry related information on Eif4e

• In summary, these data suggest that chronic alcohol consumption impairs translation initiation in muscle by altering multiple regulatory sites, including eIF2B activity and eIF4E availability [6].
• We have recently shown that reducing the protein levels of eIF-4E in CREF T24 (AS4E line) markedly decreases soft-agar colonization, increases tumor latency periods and increases tumor doubling times without significantly altering monolayer growth [7].

High impact information on Eif4e

• This subunit is present in limiting amounts in the cell, and is thought to be regulated by phosphorylation: decreased phosphorylation of eIF-4E following various treatments correlates with a decrease in cellular translation rate [8].
• We report here that overexpression of eIF-4E in NIH 3T3 and Rat 2 fibroblasts causes their tumorigenic transformation as determined by three criteria: formation of transformed foci on a monolayer of cells; anchorage-independent growth; and tumour formation in nude mice [8].
• These observations suggest that eIF-4E lies on the mitogenic signal transduction pathway, and we reasoned that overexpression of eIF-4E might profoundly affect cellular growth properties [8].
• Nonphosphorylated PHAS-I bound to initiation factor 4E (eIF-4E) and inhibited protein synthesis [9].
• Because the release of eIF4E from its binding protein as a result of phosphorylation is followed by formation of a messenger RNA cap-binding complex that includes the initiation factor eIF4G, we evaluated the association of eIF4G with released eIF4E and showed that it was increased by CCK [10].

Chemical compound and disease context of Eif4e

• The Mnk1-eIF4E pathway may provide new insights into molecular mechanisms involved in vascular hypertrophy and other Ang II-mediated pathological states [11].
• The response of brain eIF-4E concentration and phosphorylation following decapitation ischemia was studied in rat brain homogenates after electrophoresis and western blotting with antibodies against eIF-4E and phosphoserine, respectively [12].

Biological context of Eif4e

• In addition, intracellular and extracellular Ca(2+) chelators significantly inhibited H(2)O(2)-induced eIF4E phosphorylation [1].
• Eukaryotic translation initiation factor 4E (eIF4E) plays an important role in cell proliferation and differentiation [1].
• The mRNA cap-binding protein (eIF4E) is a critical integrator of cell growth and division because it is rate-limiting for translation initiation and is also rate-limiting for G(1) progression [13].
• Ischaemia induces changes in the association of the binding protein 4E-BP1 and eukaryotic initiation factor (eIF) 4G to eIF4E in differentiated PC12 cells [14].
• Here we show that eIF4E-mediated rescue from Myc-dependent apoptosis is accompanied by inhibition of mitochondrial cytochrome c release [15].

Anatomical context of Eif4e

• PGF2alpha also induced eIF4E and 4E-BP1 phosphorylation, global protein synthesis, and basic fibroblast growth factor-2 (bFGF-2) expression in VSMC [16].
• H(2)O(2) induced eIF4E phosphorylation in a dose- and time-dependent manner in growth-arrested smooth muscle cells (SMC) [1].
• The results suggest altered regulation of Erk 1/2 and p38 MAPK signal translation pathways by endogenously produced TNF, or some compound dependent on TNF may modulate, in part, the phosphorylation state of eIF4E in skeletal muscle during sepsis [2].
• Experiments achieving gain and loss of function demonstrate that eIF4E-mediated rescue is governed by pretranslational and translational activation of bcl-x as well as by additional intermediates acting directly on, or upstream of, the mitochondria [15].
• A role for PYK2 in ANG II-dependent regulation of the PHAS-1-eIF4E complex by multiple signaling cascades in vascular smooth muscle [17].

Associations of Eif4e with chemical compounds

• Despite its ability to induce eIF4E phosphorylation, H(2)O(2) had no significant effect on protein levels and new protein synthesis as compared with control [1].
• H(2)O(2)-induced eIF4E phosphorylation occurred on serine residues [1].
• PGF2alpha-induced phosphorylation of eIF4E and 4E-BP1 was also found to be sensitive to inhibition by both wortmannin and rapamycin [16].
• Similarly, SB203580, a specific inhibitor of p38 MAPK, although inhibiting H(2)O(2)-induced p38 MAPK activity, had no effect on H(2)O(2)-induced eIF4E phosphorylation [1].
• Calphostin C, a specific inhibitor of protein kinase C, also had no effect on H(2)O(2)-induced eIF4E phosphorylation [1].

Physical interactions of Eif4e

• Additionally, rapamycin prevented the stimulatory effects of leucine on eIF4E availability for binding eIF4G and inhibited leucine-dependent phosphorylation of S6K1 [18].
• Increased availability of eIF4E occurred as a consequence of diminished abundance of the inactive 4E-BP1.eIF4E complex following IGF-I [19].

Regulatory relationships of Eif4e

• Results from affinity chromatography on m7GTP-agarose demonstrated that AII-induced phosphorylation of 4E-BP1 promotes its dissociation from eIF4E in target cells [20].
• VEGF stimulated phosphorylation of Mnk1 and eIF4E and induced Mnk1 to shift from the cytoplasm to the nucleus upon phosphorylation [21].
• TGF-alpha stimulated the phosphorylation of the eukaryotic initiation factor 4E (eIF4E) but did not affect eIF2 alpha, two proteins involved in translation regulation [22].
• In contrast, inhibition of ERK2 activity by PD 098059 led to a significant loss of PGF2alpha-induced eIF4E and 4E-BP1 phosphorylation, global protein synthesis, and bFGF-2 expression [16].
• The treatment of PC12 cells with the specific p38 mitogen-activated protein kinase inhibitor SB203580 induced eIF4E dephosphorylation but did not cause any effect on protein synthesis rate [14].

Other interactions of Eif4e

• Results obtained with antibodies, immobilized PHAS-I, and a messenger RNA cap affinity resin indicated that PHAS-I did not bind eIF-4E when serine-64 was phosphorylated [9].
• Expression of dominant negative Mnk1 abrogated eIF4E phosphorylation and protein synthesis induced by VEGF [21].
• PD 98059 abrogated the TGF-alpha effect on eIF4E [22].
• In contrast, trifluoperazine, an antagonist of calcium/calmodulin kinases, completely blocked H(2)O(2)-induced eIF4E phosphorylation [1].
• Downregulation of proline-rich tyrosine kinase 2 (PYK2) by antisense oligonucleotides led to a near-complete inhibition of PHAS-1 and eIF4E phosphorylation in response to ANG II [17].

Analytical, diagnostic and therapeutic context of Eif4e

• Based on the conserved nucleotide sequences between mouse and human eIF-4E cDNA, two oligonucleotide primers for RT-PCR were synthesized chemically [23].
• In situ hybridization analysis demonstrated that elevated expression of eIF-4E mRNA was mainly observed in post-meiotic germ cells [23].
• The cloned cDNA was sequenced and used as a probe for analysis of the expression level of eIF-4E mRNA in normal, differentiated rat tissues by Northern blot analysis [23].
• Sequence analysis of the rat eIF4E promoter revealed 80% sequence similarity with human eIF4E [24].
• Isoelectric focusing was used to evaluate the phosphorylation of the initiation factor eIF4E, and Western blotting and immunoprecipitation followed by Western blotting were used to study the phosphorylation state and amount of other interacting factors [10].

References