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

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 tumorigene...

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Bibliographic Details
Published in:	Oncogene Vol. 34; no. 16; pp. 2032 - 2042
Main Authors:	Robichaud, N, del Rincon, S V, Huor, B, Alain, T, Petruccelli, L A, Hearnden, J, Goncalves, C, Grotegut, S, Spruck, C H, Furic, L, Larsson, O, Muller, W J, Miller, W H, Sonenberg, N
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 16-04-2015 Nature Publishing Group
Subjects:	631/67/322 631/80/304 631/80/84/2176 Animals Apoptosis Binding proteins Cap-binding protein Cell Biology Cell Line, Tumor Cell Movement Cell Transformation, Neoplastic - genetics Epithelial-Mesenchymal Transition Eukaryotic Initiation Factor-4E - genetics Eukaryotic Initiation Factor-4E - metabolism Female Genetic aspects Genetic translation Health aspects Human Genetics Initiation factor eIF-4E Internal Medicine Invasiveness Lung Neoplasms - genetics Lung Neoplasms - secondary Mammary gland Mammary Neoplasms, Experimental - metabolism Mammary Neoplasms, Experimental - pathology Matrix Metalloproteinase 3 - genetics Matrix Metalloproteinase 3 - metabolism Medicin och hälsovetenskap Medicine Medicine & Public Health Mesenchyme Metastases Metastasis Mice mRNA Oncology original-article Phosphorylation Protein Biosynthesis - genetics Proteins Ribonucleic acid RNA RNA, Messenger - metabolism Snail Family Transcription Factors Transcription Factors - biosynthesis Transcription Factors - genetics Transforming Growth Factor beta - metabolism Transforming growth factor-b Tumorigenesis Tumors
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Summary:	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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 These authors contributed equally.
ISSN:	0950-9232 1476-5594 1476-5594
DOI:	10.1038/onc.2014.146