Journal
ONCOGENE
Volume 34, Issue 16, Pages 2032-2042Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/onc.2014.146
Keywords
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Funding
- Susan G. Komen Breast Cancer Foundation [IIR12224057]
- Canadian Cancer Society [2010-700377]
- Cancer Research Society [2012-17280]
- PCFA [YI-0310]
- Fonds de la Recherche en Sante du Quebec [20874]
- Canadian Institutes of Health Research [220151]
- Vanier Canada Graduate Scholarship [267839]
- Swedish Research Council
- Swedish Cancer Society
- Wallenberg Academy
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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 (TGF beta) 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 TGF beta requires translational activation via the non-canonical TGF beta signaling branch acting through eIF4E phosphorylation.
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