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J. Biol. Chem. 278 (5): 3015-3022

© 2003 by The American Society for Biochemistry and Molecular Biology, Inc.

Translation Factor eIF4E Rescues Cells from Myc-dependent Apoptosis by Inhibiting Cytochrome c Release*

Shunan LiDagger , Tasaburo Takasu§, David M. PerlmanDagger , Mark S. PetersonDagger , David BurrichterDagger , Svetlana AvdulovDagger , Peter B. BittermanDagger , and Vitaly A. PolunovskyDagger

From the Dagger  Department of Medicine, University of Minnesota Medical School, Minneapolis, Minnesota 55455 and § First Department of Internal Medicine, Osaka Medical College, Takatsuki, Osaka 569-8686, Japan

Eukaryotic translation initiation factor 4E (eIF4E) markedly reduces cellular susceptibility to apoptosis. However, the mechanism by which the translation apparatus operates on the cellular apoptotic machinery remains uncertain. Here we show that eIF4E-mediated rescue from Myc-dependent apoptosis is accompanied by inhibition of mitochondrial cytochrome c release. Experiments achieving gain and loss of function demonstrate that eIF4E-mediated rescue is governed by pretranslational and translational activation of bcl-x as well as by additional intermediates acting directly on, or upstream of, the mitochondria. Thus, our data trace a pathway controlling apoptotic susceptibility that begins with the activity state of the protein synthesis machinery and leads to interdiction of the apoptotic program at the mitochondrial checkpoint.

* This work was supported by Department of Defense Grant BC98414 (to V. A. P.), National Institutes of Health Grant 2P50-HL50152 (to P. B. B.), and National Institutes of Health Grant HL 07741-07 (to S. L. and D. P.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed. Tel.: 612-624-0999; Fax: 612-625-2174; E-mail:

Copyright © 2003 by The American Society for Biochemistry and Molecular Biology, Inc.

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