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Published online April 7, 2008
doi:10.1083/jcb.200707018
The Journal of Cell Biology, Vol. 181, No. 1, 51-63
The Rockefeller University Press, 0021-9525 $30.00
© 2008 Culjkovic et al.
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Article

 The eIF4E RNA regulon promotes the Akt signaling pathway

Biljana Culjkovic1,2, Keith Tan1,2, Slobodanka Orolicki1,2, Abdellatif Amri1,2, Sylvain Meloche1,3, and Katherine L.B. Borden1,2

1 Institute for Research in Immunology and Cancer, 2 Department of Pathology and Cell Biology, and 3 Department of Pharmacology and Molecular Biology, Université de Montréal, Montréal, Québec H4M 1J6, Canada

Correspondence to Katherine L.B. Borden: katherine.borden{at}umontreal.ca

Eukaryotic initiation factor 4E (eIF4E) promotes cellular proliferation and can rescue cells from apoptotic stimuli such as serum starvation. However, the mechanisms underlying apoptotic rescue are not well understood. In this study, we demonstrate that eIF4E overexpression leads to enhanced survival signaling through Akt and that eIF4E requires Akt1 to rescue serum-deprived fibroblasts. Furthermore, a mutant form of eIF4E (W73A), which is messenger RNA (mRNA) export competent but does not promote translation, rescues cells as readily as wild-type eIF4E. We show that eIF4E mediates Akt activation via up-regulation of Nijmegen breakage syndrome 1 (NBS1), a phosphoinositide-3 kinase–Akt pathway upstream activator. Additionally, eIF4E coordinately up-regulates the expression of downstream effectors of the Akt pathway, thereby amplifying Akt signaling effects. A negative regulator of eIF4E, the promyelocytic leukemia protein (PML), suppresses Akt activation and apoptotic rescue. These PML activities likely arise, at least in part, through its inhibition of eIF4E-mediated NBS1 mRNA export. In summary, eIF4E coordinately regulates gene expression to potentiate Akt activation, an activity required for apoptotic rescue.

B. Culjkovic and K. Tan contributed equally to this paper.

Abbreviations used in this paper: 4E-BP, eIF4E-binding protein; 4E-SE, eIF4E sensitivity element; eIF4E, eukaryotic initiation factor 4E; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; m7G, 7-methyl guanosine; MEF, mouse embryonic fibroblast; MSCV, murine stem cell virus; mTOR, mammalian target of rapamycin; NBS1, Nijmegen breakage syndrome 1; ODC, ornithine decarboxylase; PI, propidium iodide; PI3K, phosphoinositide-3 kinase; PML, promyelocytic leukemia protein; qPCR, quantitative PCR; USER, untranslated sequence elements for regulation; UTR, untranslated region.


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