Importin 8 mediates m7G cap-sensitive nuclear import of the eukaryotic translation initiation factor eIF4E
Abstract
Dysregulated nuclear trafficking of oncoproteins contributes to cancer. Here, we study the trafficking of eukaryotic translation initiation factor 4E (eIF4E) in acute myeloid leukemia (AML), where eIF4E is highly elevated and accumulates in the nucleus. Nuclear eIF4E promotes export of networks of transcripts encoding oncoproteins. During clinical responses to eIF4E-targeted therapy in patients who have AML, the distribution of eIF4E becomes almost entirely cytoplasmic. At relapse, eIF4E is again mainly nuclear. Our studies provide a molecular understanding for eIF4E trafficking, through association with importin 8. We provide a molecular basis for importin 8 selectivity for certain forms of eIF4E and demonstrate the relevance of its nuclear localization to its oncogenic potential, thereby positioning the importin 8-eIF4E interaction as a novel therapeutic target.
- Publication:
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Proceedings of the National Academy of Science
- Pub Date:
- May 2016
- DOI:
- 10.1073/pnas.1524291113
- Bibcode:
- 2016PNAS..113.5263V