Translation factor eIF4E rescues cells from Myc-dependent apoptosis by inhibiting cytochrome c release.
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.
Li
Shunan
S
Department of Medicine, University of Minnesota Medical School, Minneapolis, Minnesota 55455, USA.
Takasu
Tasaburo
T
Perlman
David M
DM
Peterson
Mark S
MS
Burrichter
David
D
Avdulov
Svetlana
S
Bitterman
Peter B
PB
Polunovsky
Vitaly A
VA
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D001483:Base Sequence; D002460:Cell Line; D003574:Cytochrome c Group / Q000378:metabolism*; D017931:DNA Primers; D004622:Embryo, Mammalian; D039561:Eukaryotic Initiation Factor-4E / Q000378:metabolism*; D005347:Fibroblasts / Q000166:cytology / Q000502:physiology; D016259:Genes, myc; D007700:Kinetics; D008928:Mitochondria / Q000502:physiology; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D016133:Polymerase Chain Reaction; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D014158:Transcription, Genetic; D051020:bcl-X Protein
C494813:Bcl2l1 protein, rat; D003574:Cytochrome c Group; D017931:DNA Primers; D039561:Eukaryotic Initiation Factor-4E; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D051020:bcl-X Protein; D011065:Poly(ADP-ribose) Polymerases