title: Akt determines cell fate through inhibition of the PERK-eIF2α phosphorylation pathway.
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.
authors.affiliation: Lady Davis Institute for Medical Research, Sir Mortimer B. Davis Jewish General Hospital, Montreal, Quebec H3T1E2, Canada.
authors.forename: Zineb
authors.initials: Z
authors.lastname: Mounir
authors.forename: Jothi Latha
authors.initials: JL
authors.lastname: Krishnamoorthy
authors.forename: Shuo
authors.initials: S
authors.lastname: Wang
authors.forename: Barbara
authors.initials: B
authors.lastname: Papadopoulou
authors.forename: Shirley
authors.initials: S
authors.lastname: Campbell
authors.forename: William J
authors.initials: WJ
authors.lastname: Muller
authors.forename: Maria
authors.initials: M
authors.lastname: Hatzoglou
authors.forename: Antonis E
authors.initials: AE
authors.lastname: Koromilas
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D015153:Blotting, Western; D016923:Cell Death / Q000502:physiology*; D045744:Cell Line, Tumor; D004330:Drosophila; D059865:Endoplasmic Reticulum Stress / Q000502:physiology; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism*; D005434:Flow Cytometry; D005786:Gene Expression Regulation / Q000235:genetics / Q000502:physiology*; D047468:Immunoprecipitation; D051379:Mice; D018384:Oxidative Stress / Q000502:physiology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D019892:eIF-2 Kinase / Q000378:metabolism*
chemical_list: D015852:Eukaryotic Initiation Factor-2; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D034741:RNA, Small Interfering; D019892:eIF-2 Kinase