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

2002; Taylor & Francis; Volume: 22; Issue: 8 Linguagem: Inglês

10.1128/mcb.22.8.2853-2861.2002

1098-5549

Shunan Li, Nahum Sonenberg, Anne‐Claude Gingras, Mark S. Peterson, Svetlana Avdulov, Vitaly A. Polunovsky, Peter B. Bitterman,

Protein Kinase Regulation and GTPase Signaling

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 apoptosisbut 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.