Translational Control of Cell Fate: Availability of Phosphorylation Sites on Translational Repressor 4E-BP1 Governs Its Proapoptotic Potency

Department of Medicine, University of Minnesota Medical School, Minneapolis, Minnesota 55455, USA.
Molecular and Cellular Biology (Impact Factor: 4.78). 05/2002; 22(8):2853-61. DOI: 10.1128/MCB.22.8.2853-2861.2002
Source: PubMed


Translational control has been recently added to well-recognized genomic, transcriptional, and posttranslational mechanisms regulating apoptosis. We previously found that overexpressed eukaryotic initiation factor 4E (eIF4E) rescues cells from apoptosis, while ectopic expression of wild-type eIF4E-binding protein 1 (4E-BP1), the most abundant member of the 4E-BP family of eIF4E repressor proteins, activates apoptosis--but only in transformed cells. To test the possibility that nontransformed cells require less cap-dependent translation to suppress apoptosis than do their transformed counterparts, we intensified the level of translational repression in nontransformed fibroblasts. Here, we show that inhibition of 4E-BP1 phosphorylation by rapamycin triggers apoptosis in cells ectopically expressing wild-type 4E-BP1 and that expression of 4E-BP1 phosphorylation site mutants potently activates apoptosis in a phosphorylation site-specific manner. In general, proapoptotic potency paralleled repression of cap-dependent translation. However, this relationship was not a simple monotone. As repression of cap-dependent translation intensified, apoptosis increased to a maximum value. Further repression resulted in less apoptosis--a state associated with activation of translation through internal ribosomal entry sites. These findings show: that phosphorylation events govern the proapoptotic potency of 4E-BP1, that 4E-BP1 is proapoptotic in normal as well as transformed fibroblasts, and that malignant transformation is associated with a higher requirement for cap-dependent translation to inhibit apoptosis. Our results suggest that 4E-BP1-mediated control of apoptosis occurs through qualitative rather than quantitative changes in protein synthesis, mediated by a dynamic interplay between cap-dependent and cap-independent processes.

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Available from: Vitaly A Polunovsky, Mar 14, 2014
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    • "Initiation factor eIF4G also interacts with other factors, including eIF3 and eIF4B, to bring the mRNA to the ribosome for the initiation of translation (Clemens 2004). Overexpression of eIF4E is seen in a wide range of tumor types (Mamane and others 2004) and is associated with resistance to apoptosis (Ruggero and others 2004), whereas high-level expression of 4E-BP1 is proapoptotic (Li and others 2002). The latter protein is a key component in mediating the oncogenic effects of the Akt/ Akt and extracellular-regulated kinase signaling pathways and integrates their function in tumors (She and others 2010). "
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    • "This is at least partly because high levels of eIF4E confer resistance to apoptosis (Koromilas et al., 1992). Conversely, 4E-BP1 has been shown to have a proapoptotic effect (Li et al., 2002). Expression of the inactive phosphorylated form of 4E-BP1 has also been correlated with the state of aggressiveness of tumours (Castellvi et al., 2009) and changes in the levels of 4E-BP1 can affect the ability of tumourigenic cells to undergo apoptosis (Jeffrey et al., 2006; She et al., 2010; Nishioka et al., 2010). "
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    • "These results suggest that the PI3K/Akt/mTOR pathway would not contribute significantly to JUNV translation apart from the early activation of Akt induced by the virus previously reported (Linero and Scolaro, 2009). As mentioned above, phosphorylation of 4E-BPs, mediated by mTOR/raptor complex, promotes the release of eIF4E enabling the assembly of eIF4F complex and the eventual delivery of mRNAs to this complex (Zimmer et al., 2000; Li et al., 2002; de Benedetti and Graff, 2004). According to our results, the Fig. 7. Inhibition of PI3K/Akt/mTOR pathway does not affect JUNV multiplication. "
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