Translation initiation factor 4E blocks endoplasmic reticulum-mediated apoptosis

Shunan Li, David M Perlman, Mark S. Peterson, David Burrichter, Svetlana V Avdulov, Vitaly A Polunovsky, Peter B Bitterman

Research output: Contribution to journalArticle

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Abstract

Eukaryotic translation initiation factor 4E (eIF4E) is the mRNA cap-binding protein required for translation of cellular mRNAs utilizing the 5′ cap structure. The rate-limiting factor for mRNA recruitment to ribosomes, eIF4E is a major target for regulation of translation by growth factors, hormones, and other extracellular stimuli. When overexpressed, eIF4E exerts profound effects on cell growth and survival, leading to suppression of oncogene-dependent apoptosis, causing malignant transformation and conferring tumors with multiple drug resistance. We found previously that overexpressed eIF4E interdicts the apoptotic pathway induced by growth factor withdrawal and cytotoxic drugs by selectively activating the expression of Bcl-XL, thus preventing mitochondrial release of cytochrome c. In this study, we examined the impact of ectopic eIF4E expression on apoptosis mediated by the endoplasmic reticulum (ER). Here we show that eIF4E rescued cells from the ER stressors brefeldin A, tunicamycin, thapsigargin, and the Ca2+ ionophore A23187. In addition, we found that cells rescued from Ca2+ ionophore-triggered apoptosis did not release calcium from their ER nor did they translocate caspase-12 from the ER to the cytoplasm. These data lend strong support to the concept that eIF4E functions as a pleiotropic regulator of cell viability and that integration of critical organelle-mediated checkpoints for apoptosis can be controlled by the cap-dependent translation apparatus.

Original languageEnglish (US)
Pages (from-to)21312-21317
Number of pages6
JournalJournal of Biological Chemistry
Volume279
Issue number20
DOIs
StatePublished - May 14 2004

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Eukaryotic Initiation Factor-4E
Eukaryotic Initiation Factors
Peptide Initiation Factors
Endoplasmic Reticulum
Apoptosis
Ionophores
Cell Survival
Intercellular Signaling Peptides and Proteins
RNA Caps
RNA Cap-Binding Proteins
Caspase 12
Brefeldin A
Tunicamycin
Thapsigargin
Calcimycin
Cell growth
Protein Biosynthesis
Multiple Drug Resistance
Cytochromes c
Ribosomes

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Translation initiation factor 4E blocks endoplasmic reticulum-mediated apoptosis. / Li, Shunan; Perlman, David M; Peterson, Mark S.; Burrichter, David; Avdulov, Svetlana V; Polunovsky, Vitaly A; Bitterman, Peter B.

In: Journal of Biological Chemistry, Vol. 279, No. 20, 14.05.2004, p. 21312-21317.

Research output: Contribution to journalArticle

Li, Shunan ; Perlman, David M ; Peterson, Mark S. ; Burrichter, David ; Avdulov, Svetlana V ; Polunovsky, Vitaly A ; Bitterman, Peter B. / Translation initiation factor 4E blocks endoplasmic reticulum-mediated apoptosis. In: Journal of Biological Chemistry. 2004 ; Vol. 279, No. 20. pp. 21312-21317.
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