The eIF4E RNA regulon promotes the Akt signaling pathway.
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.
Culjkovic
Biljana
B
Institute for Research in Immunology and Cancer, Université de Montréal, Montréal, Québec H4M 1J6, Canada.
Tan
Keith
K
Orolicki
Slobodanka
S
Amri
Abdellatif
A
Meloche
Sylvain
S
Borden
Katherine L B
KL
D000818:Animals; D017209:Apoptosis; D018797:Cell Cycle Proteins / Q000378:metabolism; D002470:Cell Survival; D004268:DNA-Binding Proteins; D039561:Eukaryotic Initiation Factor-4E / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism; D051379:Mice; D041681:NIH 3T3 Cells; D009687:Nuclear Proteins / Q000378:metabolism; D000071156:Promyelocytic Leukemia Protein; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D044967:Serum / Q000378:metabolism; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D015854:Up-Regulation
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D039561:Eukaryotic Initiation Factor-4E; C466108:Nijmegen breakage syndrome 1 protein, mouse; D009687:Nuclear Proteins; C513293:Pml protein, mouse; D000071156:Promyelocytic Leukemia Protein; D012333:RNA, Messenger; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D051057:Proto-Oncogene Proteins c-akt