title: Signalling to eIF4E in cancer.
abstract: Translational control plays a critical role in the regulation of gene expression in eukaryotes and affects many essential cellular processes, including proliferation, apoptosis and differentiation. Under most circumstances, translational control occurs at the initiation step at which the ribosome is recruited to the mRNA. The eukaryotic translation initiation factor 4E (eIF4E), as part of the eIF4F complex, interacts first with the mRNA and facilitates the recruitment of the 40S ribosomal subunit. The activity of eIF4E is regulated at many levels, most profoundly by two major signalling pathways: PI3K (phosphoinositide 3-kinase)/Akt (also known and Protein Kinase B, PKB)/mTOR (mechanistic/mammalian target of rapamycin) and Ras (rat sarcoma)/MAPK (mitogen-activated protein kinase)/Mnk (MAPK-interacting kinases). mTOR directly phosphorylates the 4E-BPs (eIF4E-binding proteins), which are inhibitors of eIF4E, to relieve translational suppression, whereas Mnk phosphorylates eIF4E to stimulate translation. Hyperactivation of these pathways occurs in the majority of cancers, which results in increased eIF4E activity. Thus, translational control via eIF4E acts as a convergence point for hyperactive signalling pathways to promote tumorigenesis. Consequently, recent works have aimed to target these pathways and ultimately the translational machinery for cancer therapy.
authors.affiliation: Department of Biochemistry and Goodman Cancer Research Centre, McGill University, 1160 Pine Avenue West, Montreal, Quebec, Canada H3A 1A3.
authors.forename: Nadeem
authors.initials: N
authors.lastname: Siddiqui
authors.affiliation: Department of Biochemistry and Goodman Cancer Research Centre, McGill University, 1160 Pine Avenue West, Montreal, Quebec, Canada H3A 1A3 nahum.sonenberg@mcgill.ca.
authors.forename: Nahum
authors.initials: N
authors.lastname: Sonenberg
mesh_terms: D000818:Animals; D000846:Anniversaries and Special Events; D000970:Antineoplastic Agents / Q000627:therapeutic use; D001363:Awards and Prizes; D001671:Biochemistry; D063646:Carcinogenesis / Q000187:drug effects; D039561:Eukaryotic Initiation Factor-4E / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008954:Models, Biological; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D010442:Peptide Chain Initiation, Translational / Q000187:drug effects; D012315:RNA Caps / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D012958:Societies, Scientific; D006113:United Kingdom
chemical_list: D000970:Antineoplastic Agents; D039561:Eukaryotic Initiation Factor-4E; D009363:Neoplasm Proteins; D012315:RNA Caps; D012333:RNA, Messenger
keywords: cancer therapy; eukaryotic translation initiation factor 4E (eIF4E); eukaryotic translation initiation factor 4E-binding proteins (4E-BPs); mechanistic/mammalian target of rapamycin (mTOR); mitogen-activated protein kinase-interacting kinase 1/2 (Mnk1/2); phospho-4E