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Oncogene. 2015 Apr 16;34(16):2032-42. doi: 10.1038/onc.2014.146. Epub 2014 Jun 9.

Phosphorylation of eIF4E promotes EMT and metastasis via translational control of SNAIL and MMP-3.

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Department of Biochemistry and Goodman Cancer Research Centre, McGill University, Montreal, Quebec, Canada.
Lady Davis Institute for Medical Research, Segal Cancer Centre, Jewish General Hospital, McGill University, Montreal, Quebec, Canada.
Department of Biochemistry, Microbiology and Immunology, Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Ontario, Canada.
Signal Transduction Program, Sanford-Burnham Medical Research Institute, La Jolla, CA, USA.
Department of Anatomy and Developmental Biology, Monash University, Clayton, Victoria, Australia.
Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden.


The progression of cancers from primary tumors to invasive and metastatic stages accounts for the overwhelming majority of cancer deaths. Understanding the molecular events which promote metastasis is thus critical in the clinic. Translational control is emerging as an important factor in tumorigenesis. The messenger RNA (mRNA) cap-binding protein eIF4E is an oncoprotein that has an important role in cancer initiation and progression. eIF4E must be phosphorylated to promote tumor development. However, the role of eIF4E phosphorylation in metastasis is not known. Here, we show that mice in which eukaryotic translation initiation factor 4E (eIF4E) cannot be phosphorylated are resistant to lung metastases in a mammary tumor model, and that cells isolated from these mice exhibit impaired invasion. We also demonstrate that transforming growth factor-beta (TGFβ) induces eIF4E phosphorylation to promote the translation of Snail and Mmp-3 mRNAs, and the induction of epithelial-to-mesenchymal transition (EMT). Furthermore, we describe a new model wherein EMT induced by TGFβ requires translational activation via the non-canonical TGFβ signaling branch acting through eIF4E phosphorylation.

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