Dissecting eIF4E action in tumorigenesis

  1. Hans-Guido Wendel1,2,7,
  2. Ricardo L.A. Silva1,
  3. Abba Malina3,
  4. John R. Mills3,
  5. Hong Zhu1,
  6. Takeshi Ueda4,
  7. Rie Watanabe-Fukunaga4,
  8. Rikiro Fukunaga4,
  9. Julie Teruya-Feldstein5,
  10. Jerry Pelletier3, and
  11. Scott. W. Lowe2,6
  1. 1 Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA;
  2. 2 Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA;
  3. 3 Department of Biochemistry and McGill Cancer Center, Montreal, Quebec H3G 1Y6, Canada;
  4. 4 Department of Genetics, Osaka University, Osaka 565-0871, Japan;
  5. 5 Department of Pathology, Memorial Sloan- Kettering Cancer Center, New York, New York 10021, USA;
  6. 6 Howard Hughes Medical Institute, Cold Spring Harbor, New York 11724, USA

Abstract

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.

Keywords

Footnotes

  • 7 Corresponding author.

    7 E-MAIL wendelh{at}mskcc.org; FAX (646) 422.0197.

  • Article published online ahead of print. Article and publication date are online at http://www.genesdev.org/cgi/doi/10.1101/gad.1604407

    • Accepted October 24, 2007.
  • Freely available online through the Genes & Development Open Access option.

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