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Pause A, Belsham GJ, Gingras AC, Donze O, Lin TA, Lawrence Jr JC et al.. Insulin-dependent stimulation of protein synthesis by phosphorylation of a regulator of 5'-cap function. Nature 371: 762-767

Department of Biochemistry, McGill University, Montréal, Québec, Canada.
Nature (Impact Factor: 42.35). 11/1994; 371(6500):762-7. DOI: 10.1038/371762a0
Source: PubMed

ABSTRACT The cloning is described of two related human complementary DNAs encoding polypeptides that interact specifically with the translation initiation factor eIF-4E, which binds to the messenger RNA 5'-cap structure. Interaction of these proteins with eIF-4E inhibits translation but treatment of cells with insulin causes one of them to become hyperphosphorylated and dissociate from eIF-4E, thereby relieving the translational inhibition. The action of this new regulator of protein synthesis is therefore modulated by insulin, which acts to stimulate the overall rate of translation and promote cell growth.

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    • "An important mechanism of 4E-BP regulation is through phosphorylation, which alters their ability to interact with eIF4E. Whereas hypophosphorylated 4E-BPs strongly associate with eIF4E, phosphorylation of the 4E-BPs on multiple residues weakens their interaction with eIF4E [31]. High levels of phosphorylated 4E-BP1, which usually correlates with increased eIF4F assembly, were found in different malignancies, including breast, colorectal and prostate cancers [9] [36]. "
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    • "Hypoxia-inducible factor 1a translation is controlled through a mechanism that involves hyperphosphorylation of the eukaryotic initiation factor 4E binding protein 1 (4EBP1) (Laughner et al., 2001; Thomas et al., 2006; Duvel et al., 2010). Hypophosphorylated 4EBP1 binds to and inactivates the eukaryotic initiation factor 4E (eIF4E), thereby inducing translational inhibition (Pause et al., 1994). We assessed the phosphorylation status of 4EBP1 in WRN-depleted and control cells by western blotting. "
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    • "Another well-characterized target of mTORC1 is 4EBP1 which inhibits the initiation of protein translation by binding and inactivating the eukaryotic translation initiation factor 4E (eIF4E) (Sonenberg and Gingras, 1998). The mTORC1 phosphorylates 4EBP1 at multiple sites and this promotes the dissociation of eIF4E from 4EBP1, reducing the inhibitory effect of 4EBP1 on eIF4E-dependent translation initiation (Pause et al., 1994). Free eIF4E can form the multisubunit eIF4F complex binding to eIF4G (a large scaffolding protein), eIF4A (an ATP-dependent RNA helicase) and eIF4B, enabling cap-dependent protein translation, and inducing increased translation of mRNAs, determining G1-to-S phase transition (Faivre et al., 2006). "
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