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Molecular and Cellular Biology, April 2002, p. 2853-2861, Vol. 22, No. 8
0270-7306/02/$04.00+0     DOI: 10.1128/MCB.22.8.2853-2861.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

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

Shunan Li,1 Nahum Sonenberg,2 Anne-Claude Gingras,2 Mark Peterson,1 Svetlana Avdulov,1 Vitaly A. Polunovsky,1 and Peter B. Bitterman1*

Department of Medicine, University of Minnesota Medical School, Minneapolis, Minnesota 55455,1 Department of Biochemistry, McGill University, Montreal, Quebec H3G1Y6, Canada2

Received 17 September 2001/ Returned for modification 6 November 2001/ Accepted 14 January 2002

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.

* Corresponding author. Mailing address: Department of Medicine, University of Minnesota Medical School, MMC 276, Minneapolis, MN 55455. Phone: (612) 624-0999. Fax: (612) 625-2174. E-mail: bitte001{at}umn.edu.

Molecular and Cellular Biology, April 2002, p. 2853-2861, Vol. 22, No. 8
0022-538X/02/$04.00+0     DOI: 10.1128/MCB.22.8.2853-2861.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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