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Molecular and Cellular Biology, January 2002, p. 578-586, Vol. 22, No. 2
0270-7306/01/$04.00+0     DOI: 10.1128/MCB.22.2.578-586.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Role of Translation Initiation Factor 2B in Control of Cell Survival by the Phosphatidylinositol 3-Kinase/Akt/Glycogen Synthase Kinase 3ß Signaling Pathway

Marianna Pap1,2 and Geoffrey M. Cooper1*

Department of Biology, Boston University, Boston, Massachusetts 02215,1 Department of Biology, University Medical School of Pécs, Pécs, Hungary2

Received 4 April 2001/ Returned for modification 11 May 2001/ Accepted 15 October 2001

The phosphatidylinositol 3-kinase (PI 3-kinase)/Akt signaling pathway is an important mediator of growth factor-dependent survival of mammalian cells. A variety of targets of the Akt protein kinase have been implicated in cell survival, including the protein kinase glycogen synthase kinase 3ß (GSK-3ß). One of the targets of GSK-3ß is translation initiation factor 2B (eIF2B), linking global regulation of protein synthesis to PI 3-kinase/Akt signaling. Because of the central role of protein synthesis, we have investigated the involvement of eIF2B, which is inhibited as a result of GSK-3ß phosphorylation, in programmed cell death. We demonstrate that expression of eIF2B mutants lacking the GSK-3ß phosphorylation or priming sites is sufficient to protect both Rat-1 and PC12 cells from apoptosis induced by overexpression of GSK-3ß, inhibition of PI 3-kinase, or growth factor deprivation. Consistent with these effects on cell survival, expression of nonphosphorylatable eIF2B prevented inhibition of protein synthesis following treatment of cells with the PI 3-kinase inhibitor LY294002. Conversely, cycloheximide induced apoptosis of PC12 and Rat-1 cells, further indicating that protein synthesis was required for cell survival. Inhibition of translation resulting from treatment with cycloheximide led to the release of cytochrome c from mitochondria, similar to the effects of inhibition of PI 3-kinase. Expression of nonphosphorylatable eIF2B prevented cytochrome c release resulting from PI 3-kinase inhibition but did not affect cytochrome c release or apoptosis induced by cycloheximide. Regulation of translation resulting from phosphorylation of eIF2B by GSK-3ß thus appears to contribute to the control of cell survival by the PI 3-kinase/Akt signaling pathway, acting upstream of mitochondrial cytochrome c release.

* Corresponding author. Mailing address: Department of Biology, Boston University, 5 Cummington St., Boston, MA 02215. Phone: (617) 353-8735. Fax: (617) 353-8484. E-mail: gmcooper{at}bu.edu.

Molecular and Cellular Biology, January 2002, p. 578-586, Vol. 22, No. 2
0022-538X/01/$04.00+0     DOI: 10.1128/MCB.22.2.578-586.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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