mTORC1-Mediated Cell Proliferation, But Not Cell Growth, Controlled by the 4E-BPs

Department of Biochemistry and Goodman Cancer Research Centre, McGill University, Montreal, Quebec H3A 1A3, Canada.
Science (Impact Factor: 33.61). 05/2010; 328(5982):1172-6. DOI: 10.1126/science.1187532
Source: PubMed


The mammalian target of rapamycin complex 1 (mTORC1) integrates mitogen and nutrient signals to control cell proliferation
and cell size. Hence, mTORC1 is implicated in a large number of human diseases—including diabetes, obesity, heart disease,
and cancer—that are characterized by aberrant cell growth and proliferation. Although eukaryotic translation initiation factor
4E–binding proteins (4E-BPs) are critical mediators of mTORC1 function, their precise contribution to mTORC1 signaling and
the mechanisms by which they mediate mTORC1 function have remained unclear. We inhibited the mTORC1 pathway in cells lacking
4E-BPs and analyzed the effects on cell size, cell proliferation, and cell cycle progression. Although the 4E-BPs had no effect
on cell size, they inhibited cell proliferation by selectively inhibiting the translation of messenger RNAs that encode proliferation-promoting
proteins and proteins involved in cell cycle progression. Thus, control of cell size and cell cycle progression appear to
be independent in mammalian cells, whereas in lower eukaryotes, 4E-BPs influence both cell growth and proliferation.

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    • "The dysregulation of cap-dependent translation is causally linked to human diseases including cancer, ASDs, and fragile X syndrome (Banko et al., 2005, 2007; Boussemart et al., 2014; Gkogkas et al., 2013; Sharma et al., 2010). In cancer cells, increased eIF4E activity facilitates the translation of mRNAs coding for growth factors and oncogenic proteins (Dowling et al., 2010). In ASD and fragile X syndrome, increased synthesis of synaptic proteins results in augmented connectivity (Gkogkas et al., 2013; Sharma et al., 2010). "
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    ABSTRACT: The eIF4E-binding proteins (4E-BPs) represent a diverse class of translation inhibitors that are often deregulated in cancer cells. 4E-BPs inhibit translation by competing with eIF4G for binding to eIF4E through an interface that consists of canonical and non-canonical eIF4E-binding motifs connected by a linker. The lack of high-resolution structures including the linkers, which contain phosphorylation sites, limits our understanding of how phosphorylation inhibits complex formation. Furthermore, the binding mechanism of the non-canonical motifs is poorly understood. Here, we present structures of human eIF4E bound to 4E-BP1 and fly eIF4E bound to Thor, 4E-T, and eIF4G. These structures reveal architectural elements that are unique to 4E-BPs and provide insight into the consequences of phosphorylation. Guided by these structures, we designed and crystallized a 4E-BP mimic that shows increased repressive activity. Our studies pave the way for the rational design of 4E-BP mimics as therapeutic tools to decrease translation during oncogenic transformation. Copyright © 2015 Elsevier Inc. All rights reserved.
    Molecular Cell 02/2015; 57(6). DOI:10.1016/j.molcel.2015.01.017 · 14.02 Impact Factor
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    • "Because of their mechanism of action involving eIF4E binding, the 4E-BPs have little effect on IRES-dependent translation which is cap-independent. The 4E-BPs have been shown to play important roles in the control of cell proliferation [34], and consistent with this, their reduced expression correlates with poor patient survival [35]. An important mechanism of 4E-BP regulation is through phosphorylation, which alters their ability to interact with eIF4E. "
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    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 · 6.33 Impact Factor
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    • "We further examined two effectors of TORC1 – 4EBP and S6K – that have been widely proposed as key regulators mRNA translation. In particular, loss of 4EBP was shown to completely reverse the effect of TORC1 inhibition on mRNA translation and also to promote mammalian cell proliferation (Dowling et al., 2010; Thoreen et al., 2012). However, we observed that neither loss of 4EBP or increased levels of active S6K could maintain translation in starved larvae. "
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    ABSTRACT: The larval period of the Drosophila life cycle is characterized by immense growth. In nutrient rich conditions, larvae increase in mass approximately two hundred-fold in five days. However, upon nutrient deprivation, growth is arrested. The prevailing view is that dietary amino acids drive this larval growth by activating the conserved insulin/PI3 kinase and Target of rapamycin (TOR) pathways and promoting anabolic metabolism. One key anabolic process is protein synthesis. However, few studies have attempted to measure mRNA translation during larval development or examine the signaling requirements for nutrient-dependent regulation. Our work addresses this issue. Using polysome analyses, we observed that starvation rapidly (within thirty minutes) decreased larval mRNA translation, with a maximal decrease at 6–18 hours. By analyzing individual genes, we observed that nutrient-deprivation led to a general reduction in mRNA translation, regardless of any starvation-mediated changes (increase or decrease) in total transcript levels. Although sugars and amino acids are key regulators of translation in animal cells and are the major macronutrients in the larval diet, we found that they alone were not sufficient to maintain mRNA translation in larvae. The insulin/PI3 kinase and TOR pathways are widely proposed as the main link between nutrients and mRNA translation in animal cells. However, we found that genetic activation of PI3K and TOR signaling, or regulation of two effectors – 4EBP and S6K – could not prevent the starvation-mediated translation inhibition. Similarly, we showed that the nutrient stress-activated eIF2α kinases, GCN2 and PERK, were not required for starvation-induced inhibition of translation in larvae. These findings indicate that nutrient control of mRNA translation in larvae is more complex than simply amino acid activation of insulin and TOR signaling.
    Biology Open 10/2014; 3(11). DOI:10.1242/bio.20149407 · 2.42 Impact Factor
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