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Sci. Signal., 27 September 2011
Vol. 4, Issue 192, p. ra62
[DOI: 10.1126/scisignal.2001630]

RESEARCH ARTICLES

Akt Determines Cell Fate Through Inhibition of the PERK-eIF2α Phosphorylation Pathway

Zineb Mounir1,2*, Jothi Latha Krishnamoorthy1, Shuo Wang1, Barbara Papadopoulou3, Shirley Campbell4, William J. Muller4, Maria Hatzoglou5, and Antonis E. Koromilas1,6{dagger}

1 Lady Davis Institute for Medical Research, Sir Mortimer B. Davis Jewish General Hospital, Montreal, Quebec H3T 1E2, Canada.
2 Division of Experimental Medicine, Faculty of Medicine, McGill University, Montreal, Quebec H3A 1A3, Canada.
3 Centre de Recherche en Infectiologie, Centre Hospitalier de Québec, Pavillon CHUL, Quebec, Quebec G1V 4G2, Canada.
4 Goodman Cancer Center, McGill University, Montreal, Quebec H3G 0B1, Canada.
5 Department of Nutrition, School of Medicine, Case Western University, Cleveland, OH 44106, USA.
6 Department of Oncology, Faculty of Medicine, McGill University, Montreal, Quebec H2W 1S6, Canada.

* Present address: Department of Oncology, Novartis Institutes for BioMedical Research, 250 Massachusetts Avenue, Cambridge, MA 02139, USA.

Abstract: Metazoans respond to various forms of environmental stress by inducing the phosphorylation of the α subunit of eukaryotic translation initiation factor 2 (eIF2α) at serine-51, a modification that leads to global inhibition of mRNA translation. We demonstrate induction of the phosphorylation of eIF2α in mammalian cells after either pharmacological inhibition of the phosphoinositide 3-kinase (PI3K)–Akt pathway or genetic or small interfering RNA–mediated ablation of Akt. This increase in the extent of eIF2α phosphorylation also occurred in Drosophila cells and depended on the endoplasmic reticulum (ER)–resident protein kinase PERK, which was inhibited by Akt-dependent phosphorylation at threonine-799. The activity of PERK and the abundance of phosphorylated eIF2α (eIF2αP) were reduced in mouse mammary gland tumors that contained activated Akt, as well as in cells exposed to ER stress or oxidative stress. In unstressed cells, the PERK-eIF2αP pathway mediated survival and facilitated adaptation to the deleterious effects of the inactivation of PI3K or Akt. Inactivation of the PERK-eIF2αP pathway increased the susceptibility of tumor cells to death by pharmacological inhibitors of PI3K or Akt. Thus, we suggest that the PERK-eIF2αP pathway provides a link between Akt signaling and translational control, which has implications for tumor formation and treatment.

{dagger} To whom correspondence should be addressed. E-mail: antonis.koromilas{at}mcgill.ca

Citation: Z. Mounir, J. L. Krishnamoorthy, S. Wang, B. Papadopoulou, S. Campbell, W. J. Muller, M. Hatzoglou, A. E. Koromilas, Akt Determines Cell Fate Through Inhibition of the PERK-eIF2α Phosphorylation Pathway. Sci. Signal. 4, ra62 (2011).

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