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Monitoring eIF4F Assembly by Measuring eIF4E-eIF4G Interaction in Live Cells
Published on: May 1, 2020
Phosphorylation of eIF4E promotes EMT and metastasis via translational control of SNAIL and MMP-3
N Robichaud1, S V del Rincon2, B Huor2
1Department of Biochemistry and Goodman Cancer Research Centre, McGill University, Montreal, Quebec, Canada.
Abstract:
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.
Insights
Phosphorylation of eukaryotic translation initiation factor 4E (eIF4E) drives cancer metastasis. Inhibiting eIF4E phosphorylation prevents lung metastases and impairs invasion, revealing a key role in cancer progression.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Cancer metastasis is a major cause of mortality.
- Translational control, particularly involving eukaryotic translation initiation factor 4E (eIF4E), is crucial in cancer.
- The role of eIF4E phosphorylation in metastasis remains unclear.
Purpose of the Study:
- To investigate the role of eIF4E phosphorylation in cancer metastasis.
- To elucidate the mechanisms by which eIF4E phosphorylation influences invasion and epithelial-to-mesenchymal transition (EMT).
Main Methods:
- Utilized a mouse mammary tumor model to assess lung metastasis.
- Analyzed isolated cells for invasion capabilities.
- Investigated the effect of transforming growth factor-beta (TGFβ) on eIF4E phosphorylation and target mRNA translation.
- Examined the role of eIF4E phosphorylation in TGFβ-induced EMT.
Main Results:
- Mice with non-phosphorylatable eIF4E were resistant to lung metastases.
- Cells lacking eIF4E phosphorylation showed impaired invasion.
- TGFβ induces eIF4E phosphorylation, enhancing translation of Snail and Mmp-3 mRNAs.
- TGFβ-induced EMT requires eIF4E phosphorylation via a non-canonical signaling pathway.
Conclusions:
- eIF4E phosphorylation is essential for cancer metastasis.
- Targeting eIF4E phosphorylation may offer a therapeutic strategy against cancer spread.
- A novel model highlights the role of eIF4E phosphorylation in TGFβ-induced EMT and metastasis.
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