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
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.
- SourceAvailable from: Philippe P. Roux
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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 . High levels of phosphorylated 4E-BP1, which usually correlates with increased eIF4F assembly, were found in different malignancies, including breast, colorectal and prostate cancers  . "
ABSTRACT: Messenger RNA (mRNA) translation is highly regulated in cells and plays an integral role in the overall process of gene expression. The initiation phase of translation is considered to be the most rate-limiting and is often targeted by oncogenic signaling pathways to promote global protein synthesis and the selective translation of tumor-promoting mRNAs. Translational control is a crucial component of cancer development as it allows cancer cells to adapt to the altered metabolism that is generally associated with the tumor state. The phosphoinositide 3-kinase (PI3K)/Akt and Ras/mitogen-activated protein kinase (MAPK) pathways are strongly implicated in cancer etiology, and they exert their biological effects by modulating both global and specific mRNA translation. In addition to having respective translational targets, these pathways also impinge on the mechanistic/mammalian target of rapamycin (mTOR), which acts as a critical signaling node linking nutrient sensing to the coordinated regulation of cellular metabolism. mTOR is best known as a central regulator of protein synthesis and has been implicated in an increasing number of pathological conditions, including cancer. In this article, we describe the current knowledge on the roles and regulation of mRNA translation by various oncogenic signaling pathways, as well as the relevance of these molecular mechanisms to human malignancies. This article is part of a Special Issue entitled: Translation and Cancer. Copyright © 2014. Published by Elsevier B.V.Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms 12/2014; 1849(7). DOI:10.1016/j.bbagrm.2014.11.006 · 5.44 Impact Factor
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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. "
ABSTRACT: The Werner syndrome protein (WRN) is a nuclear protein required for cell growth and proliferation. Loss-of-function mutations in the Werner syndrome gene are associated with the premature onset of age-related diseases. How loss of WRN limits cell proliferation and induces replicative senescence is poorly understood. Here, we show that WRN depletion leads to a striking metabolic shift that coordinately weakens the pathways that generate reducing equivalents for detoxification of reactive oxygen species and increases mitochondrial respiration. In cancer cells, this metabolic shift counteracts the Warburg effect, a defining characteristic of many malignant cells, resulting in altered redox balance and accumulation of oxidative DNA damage that inhibits cell proliferation and induces a senescence-like phenotype. Consistent with these findings, supplementation with antioxidant rescues at least in part cell proliferation and decreases senescence in WRN-knockdown cancer cells. These results demonstrate that WRN plays a critical role in cancer cell proliferation by contributing to the Warburg effect and preventing metabolic stress.Aging cell 04/2014; 13(2):367-78. DOI:10.1111/acel.12181 · 5.94 Impact Factor
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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). "
ABSTRACT: The mammalian target of rapamycin (mTOR) plays an important role in the regulation of protein translation, cell growth and metabolism. The mTOR protein forms two distinct multi-subunit complexes: mTORC1 and mTORC2. The mTORC1 complex is activated by diverse stimuli, such as growth factors, nutrients, energy and stress signals; and essential signaling pathways, such as PI3K and MAPK, in order to control cell growth, proliferation and survival. mTORC1 also activates S6K1 and 4EBP1, which are involved in mRNA translation. The mTORC2 complex is resistant to rapamycin inhibitory activity and is generally insensitive to nutrient- and energy- dependent signals. It activates PKC-α and AKT and regulates the actin cytoskeleton. Deregulation of the mTOR signaling pathway (PI3K amplification/mutation, PTEN loss of function, AKT overexpression, and S6K1, 4EBP1 and eIF4E overexpression) is common in cancer, and alterations in components of the mTOR pathway have a major role in tumour progression. Therefore, mTOR is an appealing therapeutic target in many tumours. Here we summarize the upstream regulators and downstream effectors of the mTORC1 and mTORC2 pathways, the role of mTOR in cancer, and the potential therapeutic values and issues related to the novel agents targeting the mTOR-signaling pathway.British Journal of Pharmacology 04/2014; 171(16). DOI:10.1111/bph.12749 · 4.99 Impact Factor