eIF4E phosphorylation promotes tumorigenesis and is associated with prostate cancer progression.
Translational regulation plays a critical role in the control of cell growth and proliferation. A key player in translational control is eIF4E, the mRNA 5' cap-binding protein. Aberrant expression of eIF4E promotes tumorigenesis and has been implicated in cancer development and progression. The activity of eIF4E is dysregulated in cancer. Regulation of eIF4E is partly achieved through phosphorylation. However, the physiological significance of eIF4E phosphorylation in mammals is not clear. Here, we show that knock-in mice expressing a nonphosphorylatable form of eIF4E are resistant to tumorigenesis in a prostate cancer model. By using a genome-wide analysis of translated mRNAs, we show that the phosphorylation of eIF4E is required for translational up-regulation of several proteins implicated in tumorigenesis. Accordingly, increased phospho-eIF4E levels correlate with disease progression in patients with prostate cancer. Our findings establish eIF4E phosphorylation as a critical event in tumorigenesis. These findings raise the possibility that chemical compounds that prevent the phosphorylation of eIF4E could act as anticancer drugs.
Furic
Luc
L
Goodman Cancer Centre and Department of Biochemistry, Cancer Pavilion, McGill University, Montreal, QC, Canada H3A 1A3. luc.furic@mcgill.ca
Rong
Liwei
L
Larsson
Ola
O
Koumakpayi
Ismaël Hervé
IH
Yoshida
Kaori
K
Brueschke
Andrea
A
Petroulakis
Emmanuel
E
Robichaud
Nathaniel
N
Pollak
Michael
M
Gaboury
Louis A
LA
Pandolfi
Pier Paolo
PP
Saad
Fred
F
Sonenberg
Nahum
N
D000818:Animals; D018450:Disease Progression; D039561:Eukaryotic Initiation Factor-4E / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D055879:Gene Knock-In Techniques; D006801:Humans; D008297:Male; D051379:Mice; D009363:Neoplasm Proteins / Q000235:genetics; D009369:Neoplasms / Q000209:etiology* / Q000235:genetics / Q000473:pathology*; D010766:Phosphorylation / Q000502:physiology; D015854:Up-Regulation
D039561:Eukaryotic Initiation Factor-4E; D009363:Neoplasm Proteins