Dissecting eIF4E action in tumorigenesis.
Genetically engineered mouse models are powerful tools for studying cancer genes and validating targets for cancer therapy. We previously used a mouse lymphoma model to demonstrate that the translation initiation factor eIF4E is a potent oncogene in vivo. Using the same model, we now show that the oncogenic activity of eIF4E correlates with its ability to activate translation and become phosphorylated on Ser 209. Furthermore, constitutively activated MNK1, an eIF4E Ser 209 kinase, promotes tumorigenesis in a manner similar to eIF4E, and a dominant-negative MNK mutant inhibits the in vivo proliferation of tumor cells driven by mutations that deregulate translation. Phosphorylated eIF4E promotes tumorigenesis primarily by suppressing apoptosis and, accordingly, the anti-apoptotic protein Mcl-1 is one target of both phospho-eIF4E and MNK1 that contributes to tumor formation. Our results provide insight into how eIF4E contributes to tumorigenesis and pinpoint a level of translational control that may be suitable for therapeutic intervention.
Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA. wendelh@mskcc.org
Hans-Guido
HG
Wendel
Ricardo L A
RL
Silva
Abba
A
Malina
John R
JR
Mills
Hong
H
Zhu
Takeshi
T
Ueda
Rie
R
Watanabe-Fukunaga
Rikiro
R
Fukunaga
Julie
J
Teruya-Feldstein
Jerry
J
Pelletier
Scott W
SW
Lowe
D000818:Animals; D001483:Base Sequence; D015153:Blotting, Western; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D002478:Cells, Cultured; D017931:DNA Primers; D039561:Eukaryotic Initiation Factor-4E / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D005434:Flow Cytometry; D051379:Mice; D008822:Mice, Transgenic; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins / Q000235:genetics; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics
D017931:DNA Primers; D039561:Eukaryotic Initiation Factor-4E; C579094:Mcl1 protein, mouse; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; C106281:Mknk1 protein, mouse; D017346:Protein Serine-Threonine Kinases