The oncogene eIF4E reprograms the nuclear pore complex to promote mRNA export and oncogenic transformation.
The eukaryotic translation initiation factor eIF4E is a potent oncogene that promotes the nuclear export and translation of specific transcripts. Here, we have discovered that eIF4E alters the cytoplasmic face of the nuclear pore complex (NPC), which leads to enhanced mRNA export of eIF4E target mRNAs. Specifically, eIF4E substantially reduces the major component of the cytoplasmic fibrils of the NPC, RanBP2, relocalizes an associated nucleoporin, Nup214, and elevates RanBP1 and the RNA export factors, Gle1 and DDX19. Genetic or pharmacological inhibition of eIF4E impedes these effects. RanBP2 overexpression specifically inhibits the eIF4E mRNA export pathway and impairs oncogenic transformation by eIF4E. The RanBP2 cytoplasmic fibrils most likely slow the release and/or recycling of critical export factors to the nucleus. eIF4E overcomes this inhibitory mechanism by indirectly reducing levels of RanBP2. More generally, these results suggest that reprogramming the NPC is a means by which oncogenes can harness the proliferative capacity of the cell.
Institute for Research in Immunology and Cancer, Department of Pathology and Cell Biology, Université de Montréal, Québec, Canada.
Biljana
B
Culjkovic-Kraljacic
Aurélie
A
Baguet
Laurent
L
Volpon
Abdellatif
A
Amri
Katherine L B
KL
Borden
D021581:Active Transport, Cell Nucleus / Q000235:genetics; D000818:Animals; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism*; D003593:Cytoplasm / Q000235:genetics / Q000378:metabolism; D053487:DEAD-box RNA Helicases / Q000235:genetics / Q000378:metabolism; D039561:Eukaryotic Initiation Factor-4E / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D051379:Mice; D018832:Molecular Chaperones / Q000235:genetics / Q000378:metabolism; D022022:Nuclear Pore / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D028861:Nuclear Pore Complex Proteins / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D029543:Nucleocytoplasmic Transport Proteins / Q000235:genetics / Q000378:metabolism; D015513:Oncogene Proteins / Q000096:biosynthesis* / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism*
D039561:Eukaryotic Initiation Factor-4E; C474082:Gle1 protein, human; D018832:Molecular Chaperones; D028861:Nuclear Pore Complex Proteins; D009687:Nuclear Proteins; D029543:Nucleocytoplasmic Transport Proteins; D015513:Oncogene Proteins; D012333:RNA, Messenger; C091775:ran-binding protein 1; C094493:ran-binding protein 2; C121148:DDX19B protein, human; D053487:DEAD-box RNA Helicases